MX2011003833A - Highly concentrated drug particles, formulations, suspensions and uses thereof. - Google Patents

Abstract

Highly concentrated drug particle formulations are described, wherein the drug comprises between about 25 wt% and 80 wt% of the particle formulation. The particle formulations of the present invention comprise, for example, macromolecules, such as proteins and/or small molecules (such as steroid hormones). The particle formulation typically further includes one or more additional component, for example, one or more stabilizer (e.g., carbohydrates, antioxidants, amino acids, and buffers). Such concentrated particle formulations can be combined with a suspension vehicle to form suspension formulations. The suspension formulation comprises (i) a non-aqueous, single-phase vehicle, comprising one or more polymer and one or more one solvent, wherein the vehicle exhibits viscous fluid characteristics, and (ii) a highly concentrated drug particle formulation. Devices for delivering the suspension formulations and methods of use are also described. The present invention provides needed improvements in drug formulation and delivery to improve patient compliance and expand drug availability.

Description

PARTICLES OF HIGHLY CONCENTRATED DRUGS, FORMULATIONS, SUSPENSIONS AND USE OF THEM Cross Reference with Related Requests The present application claims the benefit over the US Provisional Patent Application Series No. 61 / 196,277, filed on October 15, 2008, now pending, and the Provisional US Patent Application Series No. 61 / 204,714, filed on January 9, 2009, now pending, whose applications are incorporated in its entirety to the present description for reference.

Field of the Invention The present invention relates to organic chemistry, formulation chemistry, and protein chemistry applied to pharmaceutical research and development. The aspects of the present invention provide highly concentrated drug particle formulations, suspension formulations comprising said particle formulations, apparatuses comprising said suspension formulations, and uses thereof for the treatment of diseases or conditions.

Background of the Invention Drugs, including proteins, peptides, and polypeptides tend to degrade over time in aqueous solutions, that is, they are generally unstable in an aqueous solution. Because of this chemical instability, solution drugs are often not suitable for long-term storage and use in drug delivery devices that provide for the prolonged administration of a drug. In addition, drugs with short in vivo half-lives are particularly difficult to formulate for storage and administration. Drug formulations continue to suffer from significant disadvantages limiting their use, especially with respect to their method of administration (e.g., subcutaneous or intravenous injection) and in the ability to be administered in sufficient therapeutic dosages. Improvements in drug formulation and administration are needed to improve patient compliance and expand drug availability.

Vehicles in which drugs are not dissolved but rather suspended have been shown to improve chemical stability (for example, see U.S. Patent Nos. 5,972,370 and 5,904,935). In addition, it may be beneficial to suspend the beneficial agents in a vehicle when the agent exhibits low solubility in the desired vehicle. However, suspensions may have poor physical stability due to settlement, chemical instability, and aggregation of the suspended beneficial agent. A further problem is the ability to achieve the desired concentration of the drug in the vehicle to, for example, provide prolonged administration. "Problems with non-aqueous vehicles tend to be exacerbated as drug concentrations are increased.

Several methods have been followed to achieve prolonged administration of a drug in a controlled amount. For example, Brodbeck, and associates, have described gel depot compositions that can be injected at the desired location and provide sustained release of a drug (US Patent Nos. 6,673,767, 6,468,961, 6,331,311, and 6,130,200).

Infusion pumps that can be implanted have also been described for drug administration through intravenous, intra-arterial, intrathecal, intraperitoneal, and epidural trajectories. Said pumps are generally surgically subcutaneously inserted into a pocket of tissue in the lower abdomen and provide controlled administration of a drug. A number of systems have been described for insulin administration, pain management, and administration of chemotherapy (eg, Evaluation Test / Health Services (HSTAT), External Infusion and Implantable Pumps, by Ann A. Graham, CRNA, MPH, Thomas V. Holohan, MD, Health Technology Review, No. 7, Agency for Health Care Policy and Office of Health Technology Assessment Research, January 1994 ).

Another method for the prolonged administration of a drug uses an osmotic delivery device. Said device can be implanted in a subject to release a drug in a controlled manner for a previously determined period of administration. In general, these services operate by imbibing the fluid from the external environment and releasing amounts of the drug corresponding to the fluid imbibed. An example of said osmotic delivery device is the VIADUR® device (ALZA Corporation, Mountain View, CA). The VIADUR® device is a titanium implant drug delivery system that uses DUROS® technology (ALZA Corporation, Mountain View, CA) to administer symptoms associated with advanced prostate cancer (stage 4) by administering leuprolide acetate . Treatment using the VIADUR® device reduces the amount of testosterone produced and circulated in a subject's body and provides a continuous therapy for 12 months.

For prolonged administration of a drug, dosing durations of up to one year are desirable. Such long-term storage of drugs at physiological temperatures presents many challenges. One such challenge is that the drug settlement in a liquid formulation can happen, and this could result in the heterogeneity of the drug in the suspension of the drug. Another challenge is the ability to obtain a suspension formulation that can be reliably pumped from a delivery device by a prolonged administration. A third challenge is the ability to administer high doses of the drug over time when restricted by the generally small volumes available in the delivery devices that can be implanted for drug storage. For example, the containers of the implant are generally of the order of 25 μ? at 250 μ ?.

The devices described above and the formulations have been useful for administering drugs to subjects. Although these apparatuses have found application for human and veterinary purposes, there remains a need for formulations, devices and methods of administration which have the ability to administer the drug at desired therapeutic concentrations for the prolonged duration and which provide the stability of the drug in periods of time. prolonged The highly concentrated drug particle formulations of the present invention provide solutions to many of the challenges and problems mentioned above. The present invention provides necessary improvements in, for example, drug formulation and administration to improve the longest duration, compliance of the patient, types of drugs available for use, drug stability.

Brief Description of the Invention The present invention relates generally to highly concentrated drug particle formulations and suspension formulations comprising the formulation of highly concentrated drug particles and a suspension vehicle, as well as apparatuses comprising said formulations, methods for making such formulations and devices, and methods of using them.

In one aspect, the present invention relates to highly concentrated drug particle formulations. In one embodiment, the present invention includes a particle formulation comprising from about 25% by weight to about 80% by weight of the drug and from about 75% by weight to about 20% by weight of one or more components additional, wherein the proportion of the additional components of the drug is between about 1: 1 to about 5: 1. In another embodiment, the drug comprises from about 40% by weight to about 75% by weight and one or more additional components comprise from about 60% by weight to about 25% by weight.

A particle formulation of the present invention may include components in addition to the drug component.

Examples of one or more additional components include, but are not limited to, antioxidants, carbohydrates, and regulators. In one embodiment, the ratio of the drug: antioxidant: carbohydrate: regulator is between about 2 to 20: 1 to 5: 1 to 5: 1 to 10. Examples of the antioxidant include, but are not limited to cysteine, methionine, tryptophan , and mixtures thereof. Examples of the regulators include, but are not limited to citrate, histidine, succinate, and mixtures thereof. Examples of the carbohydrates include, but are not limited to, disaccharides, for example, lactose, sucrose, trehalose, cellobiose, and mixtures thereof.

In one embodiment, the particle formulation is a spray dried particle preparation.

The drug included in the particle formulations of the present invention can be, for example, a protein or small molecule. Some embodiments of the present invention comprise the use of peptide hormones, for example, incretin mimics (eg, a glucagon-like protein (such as GLP-1), as well as analogs and derivatives thereof, exenatide (such as exendin- 4), as well as analogues and derivatives thereof); PYY (also known as a peptide tyrosine such as peptide YY), as well as analogs and derivatives thereof; oxintomodulin, as well as analogs and derivatives thereof); gastric inhibitory peptides (GIP) as well as analogs and derivatives thereof; and leptin, as well as analogues and derivatives thereof. Other embodiments comprise the use of interferon proteins (eg, alpha, beta, gamma, lambda, omega, tau, consensus, variant interferons, and mixtures thereof, as well as analogs or derivatives thereof such as pegylated forms) . Additional examples of useful proteins include recombinant antibodies, antibody fragments, humanized antibodies, single chain antibodies, monoclonal antibodies, avimers, human growth hormone, epidermis growth factor, fibroblast growth factor, growth factor. platelet-derived, transforming growth factor, nerve growth factor, and cytokines.

In one embodiment, the particles of the particle formulation are particles of between about 2 microns to about 10 microns. Generally, the particles formed, for example, by spray drying have a defined size range represented by a curve centered around an average value. In one embodiment, the curve is a bell-shaped curve and the average particle size is between about 2 microns to about 10 microns.

In a second aspect, the present invention relates to a suspension formulation comprising a highly concentrated drug particle formulation and a suspension vehicle. In one embodiment, a suspension formulation comprises a highly concentrated drug particle formulation of the present invention and a non-aqueous, single-phase suspension vehicle. The suspension vehicle generally comprises one or more polymers and one or more solvents. The suspension vehicle exhibits viscous liquid characteristics and the particle formulation is dispersed homogeneously in the vehicle.

In one embodiment, the polymer of the suspension vehicle comprises a polymer comprising pyrrolidones (e.g., polyvinyl pyrrolidone).

The solvent for a suspension vehicle can be, for example, lauryl lactate, lauryl alcohol, benzyl benzoate, or mixtures thereof.

In some embodiments, the suspension vehicle consists essentially of one or more polymers and one or more solvents. For example, the solvent may consist essentially of benzyl benzoate. The polymer can, for example, consist essentially of the polyvinyl pyrrolidone. In one embodiment, the suspension vehicle consists essentially of benzyl benzoate and a polymer comprising pyrrolidones.

The proportions of the polymer to the solvent in the suspension vehicle can be varied, for example, the suspension vehicle can comprise from about 40% by weight to about 80% by weight of the polymer and from about 20% by weight to about 60% by weight of solvents. Preferred embodiments of a suspension vehicle include vehicles formed of polymers and solvents combined in the following proportions: about 25% by weight of solvent and about 75% by weight of the polymer; about 50% by weight of the solvent and about 50% by weight of the polymer; and about 75% by weight of the solvent and about 25% by weight of the polymer.

The suspension vehicle generally has a viscosity, at a temperature of 33 ° C, of between about 5,000 to about 30,000 poises, preferably between about 8,000 to about 25,000 poises, more preferably between about 10,000 to about 20,000 poises. In one embodiment, the suspension vehicle has a viscosity of about 15,000 poises, plus or minus about 3,000 poises, at a temperature of 33 ° C.

In a third aspect, the present invention relates to an osmotic delivery device comprising a suspension formulation comprising a formulation of highly concentrated drug particles of the present invention and a suspension vehicle.

In one embodiment, an osmotic delivery device can be reduced in size and still provide for the administration of a therapeutically desired amount of a drug for a desired period of time when it is loaded with a suspension formulation comprising a highly active drug particle formulation. concentrates of the present invention.

In a fourth aspect, the present invention relates to a method of treating a disease or condition in a subject in need of such treatment using a suspension formulation comprising a formulation of highly concentrated drug particles of the present invention and a carrier of suspension. The method generally comprises administering the suspension formulation of one or more osmotic delivery devices to the subject in a substantially uniform amount for a period of about one month to about one year.

In a fifth aspect, the present invention relates to a method of manufacturing an osmotic delivery device comprising the loading of a suspension formulation, comprising a highly concentrated drug particle formulation of the present invention and a suspension vehicle. , inside a container of the osmotic delivery device.

The present invention also includes a method of manufacturing a suspension formulation, formulation of. particles, suspension vehicle, and apparatus of the present invention as described herein.

These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the present disclosure.

Brief Description of the Figures Figure 1 presents data from an in vitro release amount analysis of a Suspension Formulation 1 (described in Example 2). The figure shows the release amount per day up to 100 days at a temperature of 37 ° C with an approximate release rate of 50 μg / day (indicated as a straight line across the data points). In the figure, the vertical axis is the Drug Release Amount (μgld'a) and the horizontal axis is the Time in days.

Figure 2 presents data from the analysis of an in vitro release index of a Suspension Formulation 2 (described in Example 2). The figure shows the release amount per day up to 110 days at a temperature of 37 ° C with an approximate release rate of 75 g day (indicated as a straight line across the data points). In the figure, the vertical axis is the Drug Release Index ^ g / day) and the horizontal axis is the Time in days.

Figure 3 presents the data of the in vitro release index of Suspension Formulation 3 (described in Example 2). The figure shows the amount of release per day up to 100 days at a temperature of 37 ° C with an approximate release rate of 80 (indicated as a straight line across the data points). In the figure, the vertical axis is the Drug Release Amount ^ g / day) and the horizontal axis is the Time in days.

Figure 4 presents the in vitro release index analysis data for four omega interferon particle suspension formulations. The figure shows the amount of release per day up to 100 days at a temperature of 37 ° C with an approximate release rate (indicated as straight lines across the data points) of 10, 25, 30, and 50 μg / day. In the figure, the vertical axis is the Drug Release Amount ^ g / day), the horizontal axis is the Time in days, 10 μg / day of data indicated as rectangles, 25 data indicated as diamonds, 30 μg / day of data indicated as triangles, and 50 μg / day of data indicated as circles. The error bars are indicated for each measurement.

Figure 5 presents the data of the in vitro release index of five exenative particle suspension formulations. The figure shows the rate of release per day up to 110 days at a temperature of 37 ° C with approximate release rates (indicated as straight lines across the data points) of 5, 10, 20, 40, and 75 μg / d! a. In the figure, the vertical axis is the Drug Release Index of data indicated as diamonds, 10 μg / day of data indicated as open rectangles, 20 g day of data indicated as triangles, 40 μg / day of data indicated as circles, and 75 of data indicated as closed rectangles. The error bars are indicated for each measurement.

Figure 6A presents a schematic representation of an implantable osmotic delivery device 10 showing the basic components of the device (not to scale). In Figure 6A, the container 12 comprises inner and outer walls, wherein the outer wall comprises a lumen. A semi-permeable membrane 18 is at least partially inserted into the first end of the container, the osmotic machine is contained in the first chamber 20, wherein the first chamber is defined by a first surface of the semi-permeable membrane 18 and a first surface of a piston 14. The drug suspension formulation is contained in a second chamber 16, wherein the second chamber is defined by a second surface of the piston 14 and a first surface of the diffusion moderator 22. The diffusion moderator is at least partially inserted in a second end of the container. The diffusion moderator comprises a dispensing orifice 24. In this embodiment, the flow path 26 is formed between a threaded diffusion moderator 22 and the cords 28 formed on the inner surface of the container 12. Figure 6B presents a schematic representation of an implantable osmotic delivery device having the dimensions of approximately 45 mm in length and approximately 3.8 mm in diameter. In Figure 6B, an optional laser marking band 60 is shown and an optional external orientation slot 62 is shown. Also indicated are the container 12, the semi-permeable membrane 18, and the diffusion moderator 22. Figure 6C presents a representation Schematic of an implantable osmotic delivery device having a reduced length relative to the implantable osmotic delivery device of Figure 6B, wherein the dimensions of the device are approximately 30 mm in length and approximately 3.8 mm in diameter. In Figure 6C an optional laser marking band 60 is shown and an optional external orientation slot 62 is shown. Also indicated are the container 12, the semi-permeable membrane 18, and the diffusion moderator 22.

Detailed description of the invention All of the patents, publications, and patent applications cited in this disclosure are incorporated herein by reference as if each patent, publication, or individual patent application was specifically individually indicated to be incorporated as a reference in its entirety for all purposes. 1. 0.0 Definitions It should be understood that the terminology used in the present description is for the purpose of describing particular modalities only, and is not intended to be limiting. As used in this description and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, the reference to "a solvent" includes one or more of said solvents, the reference to "a protein" includes one or more proteins, mixtures of proteins, and the like.

Unless defined otherwise, all technical and scientific terms used in the present description have the same meaning generally understood by one skilled in the art to which the present invention pertains. Although other methods and materials similar, or equivalent, to those described herein can be used in the practice of the present invention, preferred materials and methods are described herein.

In the description and claims of the present invention, the following terminologies will be used according to the definitions set forth below.

The terms "drug", "therapeutic agent", and "beneficial agent" are used interchangeably to refer to any therapeutically active substance that is administered to a subject to produce a desired beneficial effect. In one embodiment of the present invention, the drug is a protein, for example, an interferon or an incretin mimic. In another embodiment of the present invention, the drug is a small molecule, for example, hormones such as androgens or estrogens. The apparatuses and methods of the present invention are well suited for the administration of proteins, small molecules and combinations thereof.

The terms "peptide", "polypeptide", and "protein" are used interchangeably in the present disclosure and generally refer to a molecule comprising a chain of two or more amino acids (e.g., more generally L-amino acids, but they also include, for example, D-amino acids, modified amino acids, amino acid analogs, and / or amino acid mimics). The proteins may also comprise additional groups that modify the chain of amino acids, for example, functional groups added by means of a post-translational modification. Examples of post-translational modifications include, but are not limited to, acetylation, alkylation (including, methylation), biotinylation, glutamylation, glycylation, glycosylation, isoprenylation, lipolation, phosphopantethenylation, phosphorylation, selenation, and amidation of the C-terminus. The term "protein" also includes proteins that comprise modifications of the amino terminal and / or the carboxy terminus. Modifications of the amino terminal group include, but are not limited to, des-amino modifications, N-lower alkyl, N-di-lower alkyl, and N-acyl. Modifications of the carboxy terminus include, but are not limited to, amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications (e.g., wherein the lower alkyl is Ci-C4 alkyl). The term "protein" also includes modifications, such as but not limited to those described above, amino acids between the amino and carboxy termini. In one embodiment, a protein can be modified by the addition of a small molecule.

The terminal amino acid at one end of the peptide chain generally has a free amino group (eg, the amino terminal). The terminal amino acid at the other end of the chain generally has a free carboxyl group (eg, carboxy terminal). Generally, the amino acids that form a protein are numbered in order, starting at the amino terminus and increasing their number in the direction of the carboxy terminal of the protein.

The phrase "amino acid residue" is used in the present description to refer to an amino acid that is incorporated into a protein by an amide bond or a imitation of amide bond.

The phrase "incretin imitation" as used in the present disclosure includes, but is not limited to, glucagon-like peptide 1 (GLP-1), as well as derivatives and analogs thereof, and exenatide, as well as derivatives and analogs of it. The incretin mimics are also known as "insulinotropic peptides".

The term "insulinotropic" as used in the present disclosure refers to the ability of a compound, for example, a protein, to stimulate or effect the production and / or activity of insulin (for example, an insulinotropic hormone). Such compounds generally stimulate the secretion or biosynthesis of insulin in a subject.

The term "interferon" as used in the present description includes, but is not limited to, the three major classes of human interferons: Interferon type I (e.g., interferon alpha (including alpha-2a and alpha-2b), interferon beta (including beta1-a and beta1-b), interferon omega, interferon tau, and variants thereof); Interferon type II (eg, interferon gamma, and variants thereof); and Interferon type III (for example, interferon lambda and variants thereof). In addition, the term refers to a variety of consensus interferons (e.g., in U.S. Patent Nos. 4,695,623, 4,897,471, 5,372,808, 5,541,293, and 6,013,253).

The term "vehicle" as used in the present description refers to a medium used to carry a drug. The vehicles of the present invention generally comprise components such as polymers and solvents. The suspension vehicles of the present invention generally comprise solvents and polymers which are used to prepare suspension formulations which further comprise highly concentrated drug particle formulations.

The phrase "separation phase" as used in the present description refers to the formation of multiple phases (e.g., liquid or gel phases) in the suspension vehicle, such as when the suspension vehicle makes contact with the environment. aqueous. In some embodiments of the present invention, the suspension vehicle is formulated to exhibit phase separation upon contact with an aqueous environment having less than about 10% water.

The phrase "single phase" as used in the present description refers to a solid, semi-solid, or homogeneous liquid system that is totally uniform physically and chemically.

The term "dispersed" as used in the present disclosure refers to a dispersion, suspension, or otherwise distributed compound, for example, a highly concentrated drug particle formulation, in a suspension vehicle. Generally, in non-aqueous suspension vehicles, the highly concentrated drug particle formulations of the present invention are suspended homogeneously in the vehicle, the drug particles are substantially insoluble therein. Materials that are substantially insoluble generally remain in their original physical form throughout the term due to a dosage form that contains the suspension. For example, the solid particulates of the highly concentrated drug particle formulations of the present invention generally remain as particles in non-aqueous suspension vehicles.

The phrase "chemically stable" as used in the present description refers to the formation in a formulation of no more than an acceptable percentage of degradation products produced in a period of time defined by chemical trajectories, such as deamidation (generally by hydrolysis ), aggregation or oxidation.

The phrase "physically stable" as used in the present description refers to the formation in a formulation of no more than an acceptable percentage of aggregates (e.g., dimers and other higher molecular weight products). In addition, the physically stable formulation does not change its physical state as, for example, from liquid to solid, or from amorphous to crystal form.

The term "viscosity" as used in the present description generally refers to a determined value of the ratio of the shear stress to the amount of shear (see, for example, Considine's book, DM and Considine, GD, "Encyclopedia of Chemistry "(Encyclopedia of Chemistry), 4th Edition, Van Nostrand, Reinhold, NY, 1984) essentially as follows: F / A = μ * V / L (Equation 1) where F / A = shear stress (force per unit area), μ = a constant proportionality (viscosity), and V / L = the speed by thickness of the layer (amount of cut).

From this relationship, the ratio of shear stress to shear quantity defines the viscosity. The measurements of the shear stress and the amount of shear are generally determined using the parallel plate rheometry performed under selected conditions (e.g., a temperature of about 37 ° C). Other methods for determining the viscosity include, measuring the kinematic viscosity using viscometers, for example, a Cannon-Fenske viscometer, an Ubbelohde viscometer for the Cannon-Fenske opaque solution, or an Ostwald viscometer. Generally, the suspension vehicles of the present invention have a sufficient viscosity to prevent a particulate formulation suspended therein from settling during storage and using a method of administration, for example, in a drug delivery apparatus that can be implant.

The term "non-aqueous" as used in the present description refers to a general moisture content, for example, of a suspension formulation, generally less than or equal to about 10% by weight, preferably less than or equal to about 7% by weight, more preferably less than or equal to about 5% by weight, and more preferably less than about 4% by weight.

The term "subject" as used in the present description refers to any member of the Chordata subphylum species, including, without limitation, humans and other primates, including non-human primates such as rhesus macaques and other species of monkeys and chimpanzees and other species of gorillas; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs; and birds, including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like. The term does not indicate a particular age. Therefore, it is intended to cover both adult and newborn individuals.

The term "osmotic delivery device" as used in the present description generally refers to an apparatus used for the administration of one or more beneficial agents (eg, an incretin mimic) to a subject, wherein the apparatus comprises, for example, a container (made, for example, of a titanium alloy) having a lumen containing a suspension formulation (for example, comprising an incretin imitation) and an osmotic agent formulation. A piston assembly placed in the lumen isolates the suspension formulation from the osmotic agent formulation. A semipermeable membrane placed at a distal end of the container adjacent to the osmotic agent formulation, as well as a flow modulator (which defines a delivery orifice through which the suspension formulation leaves the apparatus) which is placed in a second Distant end of the container adjacent to the suspension formulation. Generally, the osmotic delivery device is implanted within the subject, e.g., subcutaneously (e.g., inside, outside, or back of the upper arm, or the abdominal area). An exemplary osmotic delivery device is the DUROS® delivery apparatus (ALZA Corporation, Mountain View, CA).

The term "continuous administration" as used in the present description generally refers to a substantially continuous drug release from an osmotic delivery device. For example, the DUROS® delivery device releases the drug in a predetermined amount based on the principle of osmosis. The extracellular fluid enters the DUROS® device through a semipermeable membrane directly into the osmotic machine that expands to operate the piston in a slow and consistent amount of travel. The movement of the piston forces the formulation of the drug to be released through the orifice of the diffusion moderator. Therefore the release of the drug from the osmotic delivery device is continuous in a slow, controlled, consistent amount.

The term "substantially stable condition administration" as used in the present disclosure generally refers to the administration of a drug at or near the target level for a defined period of time, wherein the amount of the drug that is being administered from the device Osmotic is substantially a zero-order administration. 2. 0.0 General Review of the Present Invention Before describing the present invention in detail, it should be understood that this invention is not limited to particular types of drug administration, particular types of drug delivery devices, particular drug sources, particular solvents, particular polymers, and the like, since that the use of said particulars can be selected in view of the teachings of the present disclosure. It should also be understood that the terminology used in the present description is for purposes of describing the particular embodiments of the present invention only, and is not intended to be limiting.

The phrases "comprising", "consisting essentially of" and "consisting of" define the scope of the invention with respect to the additional components or steps not mentioned, if any, are excluded from the scope of the claim. The transition term "comprising", which is synonymous with "including", "containing", or "characterized by", is an open end and does not exclude additional elements not mentioned or steps of the method. The transition phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps and to those materials or steps that do not materially affect the basic and novel features of the present invention. The transition phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The components of the formulations and devices as well as the steps of the methods of the present invention are generally described with the "comprising" open claim language (eg, a particle formulation comprising; a suspension formulation comprising; a suspension vehicle comprising: a delivery device comprising, or a manufacturing method comprising). Said descriptions explicitly include more limited embodiments of the present invention that can be described using the transition phrase "consisting essentially of" (eg, a particle formulation consisting essentially of a suspension formulation consisting essentially of a suspending vehicle essentially, a delivery device consisting essentially of, or a manufacturing method consisting essentially of), as well as still more limited embodiments of the present invention can be described using the transition phrase "consisting of" (eg, a formulation of particles consisting of: a suspension formulation consisting of: a suspension vehicle consisting of; a delivery device consisting of; or a manufacturing method consisting of).

In one aspect, the present invention relates to highly concentrated drug particle formulations comprising a drug between about 25% by weight to about 75% by weight of the total weight of the particle formulation and one or more additional components ( for example, stabilizer). Generally the ratio of the drug to the total amount of the one or more additional components is between about 1: 3 (additional component: drug and 5: 1 (additional component: drug, eg, a ratio of 1.4: 1: 1: 2 ( drug: antioxidant: carbohydrate: regulator, where the antioxidant, carbohydrate and regulator are stabilizers) or 15: 1: 1: 1 (drug: antioxidant: carbohydrate: regulator, where the antioxidant, carbohydrate and regulator are stabilizers). In one embodiment, the particle formulation comprises approximately 40% to 50% by weight of the drug and 60% to 50% by weight of additional components (eg, stabilizers), with a ratio of the drug: additional components of about 1. to 2: 1.

The drug in the highly concentrated drug particle formulations of the present invention are generally proteins or small molecules. The one or more stabilizers are generally selected from the group consisting of carbohydrates, antioxidants, amino acids, and regulators.

In one embodiment of the present invention the drug is a protein. Examples of proteins useful in the practice of the present invention are further explained below and include, but are not limited to, the following: an interferon, such as, alpha, beta, gamma, lambda, omega, tau, consensus, interferons variants, and mixtures thereof.

Additional proteins include, but are not limited to an incretin mimic, such as, a glucagon-1-like peptide (GLP-1), a GLP-1 derivative (eg, GLP-1 (7 to 36) amide ), or a GLP-1 analog, exenatide, an exenatide derivative, or an exenatide analogue. Additional examples of useful proteins include recombinant antibodies, antibody fragments, humanized antibodies, single chain antibodies, monoclonal antibodies, avimers, human growth hormones, epidermis growth factor, fibroblast growth factor, growth factor. platelet derivative, transformation growth factor, nerve growth factor, and cytokines.

In another embodiment of the present invention the drug is a small molecule. Examples of the small molecule classes useful in the practice of the present invention are further explained below and include, but are not limited to, anti-angiogenesis inhibitors (e.g., inhibitors of thyrotoxin), microtubule inhibitors, repair inhibitors, DNA, and polyamine inhibitors. Examples of the specific small molecules useful in the practice of the present invention that are further explained below include, but are not limited to, the following: testosterone, dehydroepiandrosterone, androstenedione, androstenediol, androsterone, dihydrotestosterone, estrogen, progesterone, prednisolone, pregnenolone, estradiol, estriol, and estrone.

The highly concentrated drug particle formulation of the present invention generally includes one or more of the following additional components (e.g., stabilizers): one or more carbohydrates (e.g., lactose, sucrose, trehalose, raffinose, cellobiose, and mixtures of the same); one or more antioxidants (for example, methionine, ascorbic acid, sodium thiosulfate, ethylenediaminetetraacetic acid (EDTA), citric acid, butylated hydroxytoluene, and mixtures thereof); and one or more regulators (eg, citrate, histidine, succinate, and mixtures thereof).

In a preferred embodiment, the formulation of highly concentrated drug particles comprises a drug, a disaccharide (e.g., sucrose), an antioxidant (e.g., methionine), and a regulator (e.g., citrate). The drug generally comprises from about 20% by weight to about 80% by weight of the drug, preferably from about 25% by weight to about 75% by weight, and more preferably from about 25% by weight to about 50% by weight of the formulation of highly concentrated drug particles. The ratio of the drug to stabilizers is generally about 5: 1, preferably between about 3: 1, more preferably between about 2: 1. The formulation of highly concentrated drug particles is preferably a particle formulation prepared by spray drying and has a low moisture content, preferably less than or equal to about 10% by weight, more preferably less than or equal to about 5% in weigh. In another embodiment the particle formulation can be lyophilized.

In a second aspect, the present invention relates to a suspension formulation, which comprises the formulation of highly concentrated drug particles and a suspension vehicle. The suspension vehicle is generally non-aqueous, the single-phase suspension vehicle comprising one or more polymers and one or more solvents. The suspension vehicle exhibits viscous fluid characteristics. The particle formulation is dispersed homogeneously and uniformly in the vehicle.

The suspension vehicle of the present invention comprises one or more solvents and one or more polymers. Preferably, the solvent is selected from the group consisting of lauryl lactate, lauryl alcohol, benzyl benzoate, and mixtures thereof. More preferably, the solvent is lauryl lactate or benzyl benzoate. Preferably, the polymer comprises pyrrolidones, for example, in some embodiments the polymer is polyvinylpyrrolidone (for example, polyvinylpyrrolidone K-17, which generally has an approximate average molecular weight in a range of 7,900 to 10,800). In one embodiment of the present invention, the carrier consists essentially of benzyl benzoate and polyvinylpyrrolidone.

The suspension formulation generally has a low overall moisture content, for example, less than or equal to about 10% by weight and in a preferred embodiment less than or equal to about 5% by weight.

In another aspect, the present invention relates to an implantable drug delivery device, which comprises a suspension formulation of the present invention. In a preferred embodiment, the drug delivery device is an osmotic delivery device. In one embodiment, the present invention relates to the use of osmotic delivery devices having a general length of between about 35 mm and about 20 mm in length, preferably between about 30 mm and about 25 mm in length, more preferably about 28 mm in length. mm to 33 mm in length, and a diameter of between about 8 mm and about 3 mm, preferably a diameter of about 3.8 mm to 4 mm. In some embodiments, osmotic delivery devices having these dimensions are loaded with suspension formulations comprising the highly concentrated drug particle formulations of the present invention. In one embodiment, the osmotic delivery device has a length of about 30 mm and a diameter of about 3.8 mm.

The present invention further includes methods of manufacturing the highly concentrated drug particle formulations and / or suspension formulations of the present invention, as well as osmotic delivery apparatuses loaded with a suspension formulation of the present invention. In one embodiment, the present invention includes a method of manufacturing an osmotic delivery apparatus comprising loading a suspension formulation into a container of the osmotic delivery device.

In another aspect, the present invention relates to a method of treating a disease or condition in a subject in need of such treatment, by administering, for example, the drug from an osmotic delivery device to the subject in a substantially uniform amount by a patient. period from about a month to about a year. In one embodiment, the present invention relates to a method for the treatment of diabetes (e.g., diabetes mellitus type 2 or gestational diabetes) in a subject in need of such treatment, which comprises the administration of a formulation of highly concentrated drug of the present invention, for example, comprising an incretin mimic, of an osmotic delivery device in a substantially uniform amount. Usually, the suspension formulation is administered for a period of about one month to about one year, preferably about three months to about one year. The method may further include subcutaneously inserting an osmotic delivery device, loaded with a suspension formulation of the present invention, into the subject. Said osmotic delivery devices can also be used in treatment methods that are related to, for example, the treatment of type 2 diabetes.

In another embodiment, the present invention relates to the treatment of diseases that respond to interferon by administering the formulation of highly concentrated drug particles comprising one or more interferons. Examples of the diseases that respond to interferon include, but are not limited to, viral infections (such as, infections with the hepatitis C virus), autoimmune diseases (such as, multiple sclerosis), and certain cancers.

In another aspect, the present invention relates to a prolonged administration of the drug from a delivery device, for example, an osmotic delivery device, up to about 400 μg / aa for a period of up to about 90 days, up to about 200 μg / a for a period of up to about 180 days, or up to about 100 μl / ^ ^ ^ for a period of about one year. 3. 0.0 Formulations and Compositions 3. 1.0 Drug Particle Formulations Highly Concentrated In one aspect, the present invention provides highly concentrated drug particle formulations for pharmaceutical use. The particle formulation generally comprises from about 20% by weight to about 75% by weight of the drug and includes one or more additional components (eg, stabilizer). Examples of additional components that are stabilizing components include, but are not limited to, carbohydrates, antioxidants, amino acids, regulators, inorganic compounds, and surfactants. 3. 1.1 Example Drugs Highly concentrated drug particle formulations may comprise one or more drugs. The drug can be any physiologically or pharmacologically active substance, particularly those known to be administered to the body of a human or animal such as drugs, vitamins, nutrients, or the like. The highly concentrated drug particle formulations of the present invention are generally typical pharmaceutical formulations and can, for example, be packaged in dry form or in suspension formulations.

Drugs that can be administered by osmotic delivery systems include, but are not limited to, drugs that act on peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, the cardiovascular system, smooth muscles, the circulatory system of blood, synoptic sites, sites of neuroeffective junctions, endocrine and hormone systems, the immune system, the reproductive system, the skeletal system, autacoid systems, the food and excretion systems, the histamine system or the central nervous system. In addition, drugs that can be administered by the osmotic delivery system of the present invention include, but are not limited to, drugs used for the treatment of infectious diseases, chronic pain, diabetes, autoimmune diseases, endocrine diseases, metabolic diseases. , cancers, and rheumatologic diseases.

Generally, drugs suitable for use in highly concentrated drug particle formulations include, but are not limited to, the following: peptides, proteins, polypeptides (e.g., enzymes, hormones, cytokines), polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, steroids, analgesics, local anesthetics, antibiotic agents, anti-inflammatory corticosteroids, eye drugs, and other small molecules for pharmaceutical use (e.g., ribavirin), or synthetic analogs of these species, as well as mixtures thereof.

In one embodiment, preferred drugs include macromolecules. Said macromolecules include, but are not limited to, peptides, proteins, polypeptides, genes, genetic products, other pharmacologically active gene therapy agents, or other small molecules. In a preferred embodiment, the macromolecules are peptides, polypeptides or proteins. Described herein are numerous peptides, proteins, or polypeptides that are useful in the practice of the present invention. In addition to the peptides, proteins, and polypeptides described, modifications of these peptides, proteins, or polypeptides are also known to those skilled in the art and can be used in the practice of the present invention following the guidance presented herein. Such modifications include, but are not limited to, amino acid analogs, amino acid mimics, analogous proteins, or derived proteins. In addition, the drugs described herein can be formulated alone or in combination (e.g., mixtures).

Examples of proteins that can be formulated in the highly concentrated drug particle formulations of the present invention include, but are not limited to, the following: growth hormone; somatostatin; somatropin, somatotropin, somatotropin analogs, somatomedin-C, somatotropin plus an amino acid, somatotropin plus a protein; follicle stimulating hormones; luteinizing hormones, luteinizing hormone releasing hormones (LHRH), LHRH analogs such as leuprolide, nafarelin and goserelin, LHRH agonists or antagonists; growth hormone release factor; calcitonin; colchicine; gonadotropic release hormone; gonadotropins such as chorionic gonadotropin; oxytocin, octreotide; vasopressin; adrenocorticotrophic hormones; growth factor of the epidermis; fibroblast growth factor; platelet-derived growth factor; transformation growth factor; nerve growth factor; prolactin; cosyntropin; polyperesin polypeptides such as thyrotropin releasing hormone; Thyroid stimulation hormones; secretin; pancreozimine; enkephalin; glucagon; endocrine agents secreted internally and distributed by the bloodstream; or similar.

Additional v-proteins that can be formulated into highly concentrated drug particle formulations include, but are not limited to, the following: alpha antitrypsin; factor VII; Factor IX and other coagulation factors; insulin; peptide hormones; adrenal cortical stimulating hormones, thyroid stimulating hormones and other pituitary hormones; erythropoietin; growth factors such as granulocyte colony stimulus factor, granulocyte-macrophage colony stimulus factor, insulin-like growth factor 1; tissue plasminogen activator; CD4; 1-diamino-8-D-arginine vasopressin; Interleukin-1 receptor antagonist; tumor necrosis factor, tumor necrosis factor receptor; tumor suppressor proteins; pancreatic enzymes; lactase; cytokines, including lymphokines, chemokines or interleukins such as interleukin-1, interleukin-2; cytotoxic proteins; superoxide dismutase; and endocrine agents internally secreted and distributed in an animal through the blood stream.

In some embodiments, the drug may be one or more proteins. Examples of one or more proteins include, but are not limited to, the following: one or more proteins selected from the group consisting of recombinant antibodies, antibody fragments, antibodies humanized, single chain antibodies, monoclonal antibodies, and avimers; one or more proteins selected from the group consisting of human growth hormone, epidermis growth factor, fibroblast growth factor, platelet derived growth factor, transformation growth factor, and nerve growth factor; and one or more cytokines.

Some embodiments of the present invention comprise the use of peptide hormones, for example, incretin imitation (eg, glucagon-like proteins (such as GLP-1), as well as analogs and derivatives thereof, exenatide (such as exendin- 4), as well as analogues and derivatives thereof); PYY (also known as peptide YY, tyrosine peptide), as well as analogs and derivatives thereof; oxintomodulin, as well as analogs and derivatives thereof); gastric inhibitory peptide (GIP) as well as analogs and derivatives thereof; and leptin, as well as analogs and derivatives thereof. Other embodiments comprise the use of interferon proteins (eg, alpha, beta, gamma, lambda, omega, tau, consensus, interferon variants, and mixtures thereof, as well as analogs or derivatives thereof such as pegiladas, see, for example, the book "The Interferons: Characterization and Application." {The Interferons: Characterization and Application), Anthony Meager (Editor), Wiley-VCH (May 1, 2006)).

GLP-1 (including three forms of the peptide, GLP-1 (1-37), GLP-1 (7-37) and GLP-1 (7-36) amide, as well as GLP-1 analogues) have been shown to stimulate insulin secretion (ie, they are insulinotropic) which induce glucose uptake by the cells and result in decreases in serum glucose levels (see, for example, Mojsov, S., Int. J Peptide Protein Research, 40: pages 333 to 343 (1992)).

Numerous GLP-1 derivatives and analogs demonstrating an insulinotropic action are known in the art (see, for example, U.S. Pat. Nos. 5,118,666 5,120,712; 5,512,549; 5,545,618; 5,574,008 5,574,008 5,614,492; 5,958,909; 6,191,102; 6,268,343 6,329,336 6,451,974; 6,458,924; 6,514,500; 6,593,295 6,703,359 6,706,689; 6,720,407; 6,821,949; 6,849,708 6,849,714 6,887,470; 6,887,849; 6,903,186; 7,022,674 7,041, 646,084,243; 7,101,843; 7,138,486; 7,141,547 7,144,863 and 7,199,217). Examples of the GLP-1 derivatives and analogs include, but are not limited to, SYNCRIA® (GlaxoGroup Limited, Greenford, Middlesex, UK) (pharmaceutical albiglutide), pharmaceutical taspoglutide (Hoffmann-La Roche Inc.), and VICTOZA® (Novo Nordisk A / S LTD, Bagsvaerd, DK) (liraglutide) pharmaceutical. Accordingly, for ease of reference in the present disclosure, the family of GLP-1 derivatives and analogs having insulinotropic activity we refer to them collectively as "GLP-1".

Exendin-3 and exendin-4 are known in the art (Eng, J., and associates, J. Biol. Chem., 265: pages 20259 to 20262 (1990); Eng., J., and associates, J. Biol. Chem., 267: pages 7402 to 7405 (1992)). The use of exendin-3 and exendin-4 has been proposed for the treatment of type 2 diabetes and the prevention of hyperglycemia (see, for example, US Pat. No. 5,424,286). Numerous exendin-4 derivatives and analogs (including, for example, exendin-4 agonists) are known in the art (see, for example, US Patent Nos. 5,424,286, 6,268,343, 6,329,336, 6,506,724, 6,514,500, 6,528,486, 6,593,295; 6,703,359; 6,706,689; 6,767,887; 6,821,949; 6,849,714; 6,858,576; An example of an exendin derivative or analog is lixisenatide (Sanofi-Aventis). Exenatide is a synthetic version of exendin-4 (Kolterman O.G., and associates, J. Clin Endocrinol, Metab.88 (7): pages 3082 to 3089 (2003)). Accordingly, and for ease of reference in the present disclosure, the family of exenatide, exendin-4 (for example, exendin-4 or exendin-4-amide), exendin-4 derivatives, and exendin-4 analogs they are referred to collectively as "exenatida".

PYY is a peptide amide of 36 amino acid residues. PYY inhibits small bowel mobility and blood flow (Laburthe, M., Trends Endocrinol Metab.1 (3): pages 168 to 174 (1990), the carrier of intestinal secretion (Cox, HM, and associates, Br J Pharmacol 101 (2): pages 247 to 252 (1990); Playford, RJ, and associates, Lancet 335 (8705): pages 1555 to 1557 (1990)), and stimulate net uptake (MacFayden, RJ, and associates , Neuropeptides 7 (3): pages 219 to 227 (1986).) The sequence of PYY, as well as analogs and derivatives thereof, are known in the art (for example, see U.S. Patent Nos. 5,574,010 and 5,552,520).

Oxintomodulin is a 37-amino acid peptide hormone that occurs naturally found in the colon that has been found to suppress appetite and facilitate weight loss (Wynne K, and associates, Int J Obes (Lond) 30 (12): pages 1729 to 1736 (2006)). The oxintomodulin sequence, as well as analogs and derivatives thereof, are known in the art (for example, U.S. Patent Publication Nos. 2005-0070469 and 2006-0094652).

GIP is an insulinotropic peptide hormone (Efendic, S., and associates, Horm Metab Res. 36: pages 742 to 746 (2004)) and is secreted by the duodenum and jejunum mucosa in response to fat and absorbed carbohydrates that stimulate the pancreas to secrete insulin. The GIP circulates as a protein of 42 biologically active amino acids. GIP is known both as gastric inhibitory peptide and insulin-dependent peptide of glucose. GIP is a 42 amino acid gastrointestinal regulatory peptide that stimulates insulin secretion from pancreatic beta cells in the presence of glucose (Tseng, C, and associates, PNAS 90: pages 1992 to 1996 (1993)). The sequence of the GIP, as well as the analogs and derivatives thereof, are known in the art (eg, eier JJ., Diabetes Metab Res Rev. 21 (2): pages 91 to 117 (2005); Efendic S., Horm Metab Res. 36 (11-12): pages 742 to 746 (2004)).

Leptin is a 16 kDaltons protein hormone that plays a key role in the regulation of energy uptake and energy expenditure, including appetite and metabolism (Brenhan, et al., Nat Clin Pract Endocrinol Metab 2 (6): pages 318 to 327 (2006)). The leptin protein (encoded by the Obese gene (Ob)), analogues, and derivatives that have been processed to be used as modulators for the control of weight and adiposity of animals, including mammals and humans. The sequence of leptin, as well as analogs and derivatives thereof, are known in the art (for example, U.S. Patent Nos. 6,734,106; 6,777,388; 7,307,142; and 7,112,659; International Publication.

The highly concentrated drug particle formulations of the present invention are exemplified using an incretin mimic and an interferon (example 1). These examples are not intended to be limiting.

In another embodiment, preferred drugs include modified proteins including, but not limited to, hybrid proteins (eg, fusions in the frame of coding sequences of two or more proteins or two or more chemically conjugated proteins), small molecules linked to a protein (for example, delivery portions to the target linked to the therapeutic protein, therapeutic small molecule linked to a target delivery protein, combinations of delivery portions to the target, therapeutic small molecules, targeting proteins and therapeutic proteins). Examples of the hybrid proteins include but are not limited to, exenatide / PYY, oxyntomodulin / PYY, monoclonal antibodies / cytotoxic proteins, albumin fusion proteins (eg, GLP-1 / albumin) and exenatide / oxyntomodulin / PYY. Examples of small molecules linked to proteins include, but are not limited to, cytotoxic drugs / monoclonal antibodies (eg, vinblastine, vincristine, doxorubicin, colchicine, actinomycin D, etoposide, taxol, puromycin and gramicidin D).

In another embodiment, preferred drugs include small molecules. Examples of drugs that can be used in the practice of the present invention include, but are not limited to the following: hypnotics and sedatives such as sodium pentobarbital, phenobarbital, secobarbital, thiopental, amides and ureas exemplified by diethylisovaleramide and alphabromoisovaleryl urea, urethanes or disfulphanes, heterocyclic hypnotics such as dioxopiperidines, glutarimides, antidepressants such as isocarboxazide, nialamide, phenelzine, imipramine, tranylcypromide, pargyline), tranquilizers such as chloropromazine, promazine, reserpine, fluphenazine, deserpidine, meprobamate, benzodiazepines such as chlordiazepoxide; anticonvulsants such as primidone, diphenylhydantoin, ethyltoin, pheneturide, ethosuximide, muscle relaxants and anti-parkinsonian agents such as mephenesin, methocarbomol, triexylphenidyl, biperiden, levo-dopa, also known as L-dopa and L-beta-3-4-dihydroxyphenylalanine , analgesics such as morphine, codeine, meperidine, nalorphine, antipyretics and anti-inflammatory agents such as aspirin, salicylamide, sodium salicylamide, naproxen, ibuprofen, local anesthetics such as, procaine, lidocaine, naepain, piperocaine, tetracaine, dibucaine, antispasmodics and anti-ulcer agents such as, atropine, scopolamine, metscopolamine, oxyphenon, papaverine, prostaglandins such as PGEL PGE2, PGF1A | FA, PGF2aifa, PGA; antimicrobials such as penicillin, tetracycline, oxytetracycline, chlorotetracycline, chloramphenicol, sulfonamides, tetracycline, bacitracin, chlortetracycline, erythromycin, isoniazid, rifampin, ethambutol, pyrazinamide, rifabutin, rifapentine, cycloserine, ethionamide, streptomycin, amikacin / kanamycin, capreomycin, p-acid aminosalicylic, levofloxacin, moxifloxacin and gatifloxacin, antimalarial drugs such as 4-aminoquinolines, 8-aminoquinolines, pyrimethamine, chloroquine, sulfadoxine-pyrimethamine, mefloquine, atovaquone-proguanil, quinine, doxycycline, artemisinin (a sesquiterpene lactone) and derivatives , anti-Leishmaniasis agents (for example, meglumine, antimonate, sodium stibogluconate, amphotericin, miltefosine and paromocin), anti-trypanosomiasis agents (for example, benzinidazole and nifurtimox), anti-amebiasis agents for example, (metronidazole, tinidazole and fluorate of diloxanide), anti-protozoan disease agents (e.g., eflornithine, furazolidone, melarsoprol, metronidazole, ornidazole, parmomycin sulfate, pentamidine, pyrimethamine and tinidazole); hormonal agents such as, prednisolone, cortisone and triamcinolone, androgenic spheroids, (eg, methyltestosterone, fluoxmesterone), estrogenic steroids (eg, 17-beta-estradiol and tinil estradiol), progestational steroids (eg, 17-alpha-hydroxyprogesterone) acetate, 19-nor-progesterone, norethindrone), sympathomimetic drugs, such as epinephrine, amphetamine, ephedrine, norepinephrine, cardiovascular drugs such as procainamide, amyl nitrate, nitroglycerin, dipyridamole, sodium nitrate, mannitol nitrate, diuretics such as acetazolamide , chlorothiazide, flumetiazide, anti-parasitic agents such as befenium hydroxynatodate, dichlorophene, enitabates, dapsone, neoplastic agents such as mechlorethamine, uracil mustard, 5-fluorouracil, 6-thioguanine and procarbazine, hypoglycemic drugs such as insulin-related compounds (for example, insulin isophane suspension, suspension of protamines d zinc, insulin, zinc globin insulin, extended zinc insulin suspension) tolbutamide, acetohexamide, tolazamide, chlorpropamide, nutritional agents such as, vitamins, essential amino acids and essential fats; eye drugs such as pilocarpine base, pilocarpine hydrochloride, pilocarpine nitrate, antiviral drugs such as disoproxil fumarate, acyclovir, cidofovir, docosanol, famciclovir, fomivirsen, foscarnet, ganciclovir, idoxuridine, penciclovir, trifluridine, tromantadine, valaciclovir, valganciclovir , vidarabine, amantadine, arbidol, oseltamivir, peramivir, rimantadine, zanamivir, abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine, zidovudine, tenofovir, efavirenz, delavirdine, nevirapine, loviride, amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir , nelfinavir, ritonavir, saquinavir, tipranavir, enfuvirtide, adefovir, fomivirsen, imiquimod, inosine, podophyllotoxin, ribavirin, viramidine, fusion blockers specifically targeting viral surface proteins or viral receptors (eg, gp-41 inhibitor, (T-20), CCR-5 inhibitor); anti-nausea drugs such as scopolamine, dimenhydrinate), yodoxuridine, hydrocortisone, eserine, phospholine, iodide, as well as other beneficial drugs.

In one embodiment of the present invention, the spheroids are incorporated into the highly concentrated drug particle formulations of the present invention (eg, testosterone, dehydroepiandrosterone, androstenedione, androstenediol, androsterone, dihydrotestosterone, estrogen, progesterone, prednisolone, pregnenolone, estradiol , estriol, estrone and mixtures thereof.

Various forms of the above drugs can be used in the highly concentrated drug particle formulations in the present invention including, but not limited to, the following uncharged molecules, molecular complex components; and pharmacologically acceptable salts such as hydrochloride, hydrobromide, sulfate, laurate, palmitate, phosphate, nitrate, borate, acetate, maleate, tartrate, oleate and salicylate. For acidic drugs, the salts of metals, amines or organic cations, for example, quaternary ammonium can be used. In addition, simple derivatives of drugs such as esters, ethers, amides and the like having solubility characteristics suitable for purposes of the invention may also be used in the present invention.

In another embodiment, combinations of small molecules can be incorporated into the highly concentrated drug particle formulations of the present invention. One or more of said small molecules can be incorporated individually of one or more highly concentrated drug particle formulations of the present invention and used alone or in combination. As another example, two or more small molecules can be conjugated and the combined small molecules formulated in the highly concentrated drug particle formulations of the present invention (eg, Vinca alkaloids conjugated to folate, Reddy, et al., Cancer Res. 67 (9): pages 4434-4442 (2007)).

The highly concentrated drug particle formulations of the present invention can be included in different dosage forms for pharmaceutical administration, such as solution, dispersion, paste, cream, particles, granules, tablets, emulsions, suspensions, powders and the like. In addition to one or more drugs, the drug formulation may additionally include pharmaceutically acceptable carriers and / or additional components such as antioxidants, stabilizing agents, regulators and permeation enhancers. In a preferred embodiment, the highly concentrated drug particle formulations of the present invention are used to form suspension formulations for use in osmotic delivery devices.

The above drugs and other drugs known to those skilled in the art are useful in the methods of treatment for a variety of diseases and conditions including but not limited to the following: chronic pain, hemophilia and other blood disorders, endocrine diseases, diseases of growth, metabolic diseases, rheumatological diseases, diabetes (including type 2 diabetes), leukemia, hepatitis, renal failure, infectious diseases (including bacterial infections, viral infections (eg, human immunodeficiency virus infection, hepatitis C, hepatitis B, yellow fever, West Nile, Dengue, Marburg, Ebola, etc.) infections by parasites), hereditary diseases such as deficiency of cerbrosidase and deficiency of adenosine deaminase) hypertension, septic shock, autoimmune diseases (for example, Graves' disease, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis), shock and wasting diseases, cystic fibrosis, lactose intolerance, Crohn's disease, inflammatory bowel disease, gastrointestinal cancers (colon cancers and cancer) rectal), breast cancer, leukemia, lung cancer, bladder cancer, kidney cancer, non-Hodgkin lymphomas, pancreatic cancer, thyroid cancer, endometrial cancer, prostate cancer and other cancers. Some of the above agents are useful for the treatment of infectious diseases that require chronic treatments including, but not limited to, tuberculosis, malaria, leishmaniasis, trypanosomiasis (sleeping sickness) and Chaga disease), and parasitic worms.

The amount of drugs in the highly concentrated drug particle formulations is the amount needed to administer a therapeutically effective amount of the agent to achieve the therapeutic result at the site of administration. In practice, this will vary depending on some variables for example, such as the particular agent, the site of administration, the severity of the disease and the desired therapeutic effect. The beneficial agents and their dosage unit amounts are known in the prior art, in Goodman and Gilman's books "The Pharmacological Basis of Therapeutics" (The Pharmacological Basis of Theapeutics) (eleventh edition, (2005), CG Hill " Remington Pharmaceutical Sciences (Remington's Pharmaceutical Sciences) (eighteenth edition (1995) Mack Publishing Co .; and Martin's "Pharmaceutical Sciences and Physical Pharmacy, (Physical Pharmacy and Pharmaceutical Sciences) (first edition (2005), Lippincott Williams and Wilkins Generally, for an osmotic delivery system, the volume of the chamber comprising the drug formulation is between about 100 μm and about 1000 μm, and more preferably between about 140 μm and about 200 μm. In one embodiment, the volume of the chamber comprising the drug formulation is approximately 150 μ ?.

The highly concentrated drug particle formulations of the present invention are preferably chemically and physically stable for at least about one month, at least about 1.5 months, and preferably at least about 3 months, preferably at least about 6 months, more preferably at least about 9 months, and more preferably at least about 12 months at the temperature of administration. The administration temperature is generally the normal temperature of the human body, for example, of about 37 ° C, or slightly higher, for example, of about 40 ° C. moreover, the highly concentrated drug particle formulations of the present invention are preferably chemically and physically stable for at least about 3 months, preferably at least about 6 months, more preferably at least about 12 months at storage temperature. Examples of storage temperature include cooling temperature, for example, of about 5 ° C, or room temperature, for example, of about 25 ° C.

Highly concentrated drug particle formulations can be considered chemically stable and less than about 25%, preferably less than about 20%, more preferably less than about 15%, more preferably less than about 10% and more preferably less of about 5%, the decomposition products of the drug particles are formed even after about 3 months, preferably after about 6 months, preferably after about 12 months at administration temperature and after about 6 months, after approximately 12 months and preferably after approximately 24 months in storage temperature.

A formulation of highly concentrated drug particles can be considered physically stable if less than about 10%, less than about 5% and more preferably less than about 3%, more preferably less than about 1%, the drug aggregates they are formed after about 3 months, preferably after about 6 months, at administration temperature and about 6 months, preferably about 12 months, at storage temperature.

Example 3A presents exemplary data related to the stability of the highly concentrated drug particle formulations of the present invention.

When the drug in the formulation of highly concentrated drug particles is a protein, the protein solution is maintained in a frozen condition using spray drying to a solid condition. The Tg (temperature in transition to glass) may be a factor to consider in order to achieve a stable protein composition. Although we do not intend to be compromised by any particular theory, the theory of formation of a high Tg amorphous solid to stabilize the peptides, polypeptides and protein has been used in the pharmaceutical industry. Generally, if an amorphous solid has a higher Tg such as 100 ° C, the proteins will not be mobile when stored at room temperature and still up to the temperature of 40 ° C because the storage temperature is below the Tg. . Calculations using molecular information have shown that if a glass transition temperature is above a storage temperature of 50 ° C, there is a zero mobility of the molecules. The zero mobility of the molecules correlates with better stability. The Tg also depends on the moisture level in the product formulation. Generally, to a wetter product, a lower Tg of the composition.

Accordingly, in some aspects of the present invention, excipients with higher Tg may be included in the protein formulation to improve stability, for example, sucrose (Tg = 75 ° C) and trehalose (Tg = 110 ° C) . Preferably, the particle formulations can be formed into particles using processes such as spray drying, lyophilization, desiccation, frozen drying, grinding, granulation, ultrasonic droplet creation, crystallization, precipitation and other techniques available in the art of forming particles from a mixture of components. The particles are preferably substantially uniform in shape and size.

A typical spray drying process may include, for example, the loading of a spray solution containing a small molecule or protein, for example, an incretin mimic (eg, exenatide, example 1), and stabilization excipients in a sample camera. The sample chamber is generally maintained at a desired temperature, for example, cooling to room temperature. Refrigeration normally promotes the stability of the drug. A solution, emulsion or suspension is introduced to the spray dryer where the liquid is atomized into droplets. The droplets can be formed by the use of a rotary atomizer, pressure nozzle, pneumatic nozzle or sonic nozzle. The mist of droplets is immediately contacted within a drying gas in a drying chamber. The drying gas removes the solvent from the droplets and is the carrier of the particles within a collection chamber. In spray drying, factors that may affect performance include, but are not limited to, localized charges in the particles (which may promote adhesion of the particles to the spray dryer), and the aerodynamics of the particles (in which it can be difficult to collect the particles). In general, the performance of the spray drying process depends in part on the particle formulation.

In one embodiment of the present invention, the particles are sized so that they can be administered by means of osmotic drug delivery devices that can be implanted. The shape and size of the particles generally helps to produce a consistent and uniform amount of release of said delivery device; however, a particle preparation having a non-normal particle size distribution in its profile can also be used. For example, the typical implantable osmotic delivery device having a delivery port, the size of the particles is less than about 30%, more preferably less than about 20%., more preferably less than about 10% of the diameter of the delivery port. In one embodiment of the particle formulation for use with an osmotic delivery system, wherein the diameter of the delivery port of the implant is about 0.5 mm, the sizes of the particles may be, for example, less than about 150 microns up to 50 microns. In one embodiment, the formulation of the particles for use with an osmotic delivery system, wherein the diameter of the delivery port of the implant is about 0.1 mm, the particle sizes can be, for example, less than about 30 microns up to approximately 10 microns. In one embodiment, the orifice is about 0.25 mm (250 microns) and the particle size is from about 2 microns to about 5 microns.

Generally, the particles of the particle formulations of the present invention when incorporated in a suspension vehicle do not settle in less than about 3 months, preferably do not settle in less than about 6 months, more preferably do not settle in less than approximately 12 months, and more they preferably do not settle in less than about 24 months at the temperature of administration, and even more preferably do not settle in less than about 36 months at the temperature of administration. Suspension vehicles generally have a viscosity between about 5000 and about 30,000 poises; preferably between about 8000 and about 25,000 poises, preferably between about 10,000 and about 20,000 poises. In one embodiment, the suspension vehicle has a viscosity of about 15,000 poises plus or minus about 3,000 poises. Generally speaking, smaller particles tend to have a lower settlement amount in viscous suspension vehicles than larger particles. Therefore, nano-sized micron particles are generally desired. Based on simulation modeling studies, particles of viscous suspension formulation from about 2 microns to about 10 microns of the present invention are not expected to settle for at least 20 years at room temperature. In one embodiment of the particle formulation of the present invention, for use in an implantable osmotic delivery device comprises particles of sizes less than about 50 microns, more preferably less than about 10 microns, more preferably in a range of approximately 2 to approximately 7 microns In one embodiment, a formulation of highly concentrated drug particles of the present invention comprises one or more drugs, as described above, and one or more additional components (e.g., one or more stabilizers). The stabilizers can be, for example, carbohydrates, antioxidants, amino acids, regulators, inorganic compounds or surfactants. The amounts of stabilizers and regulator in the formulation of particles can be determined experimentally based on the activities of the stabilizers and regulators and the desired characteristics of the formulation, generally, the amount of carbohydrates in the formulations is determined by means of the problems of aggregation . In general, the level of carbohydrates should not be too high to avoid the promotion of crystal growth, in the presence of water due to excess carbohydrates not linked to the drug. Generally, the amount of antioxidant in the formulation determined by the oxidation concerns, while the amount of amino acids in the formulation is determined by the concerns of oxidation and / or the ability of particle formation during spray drying. Generally, the amount of regulator in the formulation is determined by pre-process concerns, stability concerns and the ability of particle formation during spray drying. The regulator may be required to stabilize the drug during processing, for example, the preparation of the solution and spray drying, when all the excipients are solubilized.

Examples of the carbohydrates that may be included in the particle formulation include, but are not limited to, monosaccharides (e.g., fructose, maltose, galactose, glucose, D-mannose and sorbose), disaccharides, (e.g., lactose, sucrose, trehalose and cellobiose), polysaccharides (e.g., raffinose, melezitose, maltodextrin, dextrans and starches) and alditols (e.g., acyclic polyols, e.g., mannitol, xylitol, maltitol, lactitol, xylitol sorbitol, pyranosyl sorbitol and myoesitol). Preferred carbohydrates include disaccharides and / or non-reductive sugars such as sucrose, trehalose and raffinose.

Examples of antioxidants that may be included in the particle formulation include, but are not limited to, methionine, ascorbic acid, sodium thiosulfate, catalase, platinum, ethylenediaminetetraacetic acid (EDTA), citric acid, cysteines, thioglycerol, thioglycolic acid, thiosorbitol, butylated hydroxanisol, butylated hydroxyltoluene and propyl gallate. In addition, amino acids that are easily oxidized can be used as antioxidants, for example, cysteine, methionine and tryptophan. A preferred antioxidant is methionine.

Examples of the amino acids that can be included in the particle formulation include but are not limited to, arginine, methionine, glycine, histidine, alanine, L-leucine, glutamic acid, iso-leucine, L-threonine, 2-phenylamine, valine, norvaline, praline, phenylalanine, tryptophan, serine, asparagine, cysteine, tyrosine, lysine and norleucine. Preferred amino acids include those that are readily oxidized, for example, cysteine, methionine and tryptophan.

Examples of the regulators that can be included in the particle formulation include, but are not limited to, citrate, histidine, succinate, phosphate, maleate, tris, acetate, carbohydrate and gly-gly. Preferred regulators include citrate, histidine, succinate and tris.

Examples of the inorganic compounds that may be included in the particle formulation include, but are not limited to, NaCl, Na 2 SO 4, NaHCO 3, KCl, KH 2 PO 4, CaCl 2, and MgCl 2.

In addition, the particle formulation may include other excipients, such as surfactants and salts. Examples of the surfactants include, but are not limited to, polysorbate 20, polysorbate 80, PLURONIC® (BASF Corporation, Mount Olive, NJ) F68, and docecyl sodium sulfate (SDS). Examples of the salts include, but are not limited to Sodium chloride, calcium chloride and magnesium chloride.

All the components included in the general particle formulation are acceptable for pharmaceutical use in mammals, in particular in humans.

Table 1 below presents examples of particle formulation composition ranges for particles comprising a protein (ranges of values of about, for example, in the "Range" column, the protein is present at about 25% by weight up to about 80% by weight). Although preferred embodiments include proteins, carbohydrates, antioxidants and / or amino acids, and regulators, some embodiments may, for example, include only proteins and carbohydrates; proteins and antioxidants, proteins and regulator, protein, carbohydrate and antioxidant; protein, carbohydrate and regulator; protein, antioxidant and regulator; wherein the weight percent range of the protein is provided in Table 1, and the remaining weight percent is formed by additional selected components. Accordingly, in some embodiments, the particle formulation may comprise selected components and in other embodiments, consist essentially of selected components. In addition, as explained above, the particle formulations of the present invention may comprise additional excipients and / or stabilizers. The preferred embodiments of the present invention consist essentially of proteins, in the approximate weight percent ranges presented in Table 1, plus the stabilizers selected (eg, carbohydrate and / or antioxidant and / or amino acid and / or regulator, as well as combinations thereof) for bring the percentage in total weight to essentially 100%. Small molecules can also be formulated as described here. Generally, the typical weight percentage of a selected small molecule is in the same ranges presented in Table 1 for the proteins.

Table 1 Some preferred levels of particle loads in suspension formulation are less than about 40%, less than about 30%, less than about 20% and less than about 10%, where the typical lower levels of particle loads in the suspension formulations are greater than about 0.1%, greater than about 1% and preferably greater than about 5%. Various exemplary embodiments of highly concentrated drug particle formulations of the present invention are set forth in Example 1, wherein the drug is a protein.

Table 2 below presents examples of particle formulation composition ranges for particles comprising an incretin mimic, such as, glucagon-like peptides-1 (GLP-1), a GLP-1 derivative (eg, GLP- 1 (7-36) amide), or a GLP-1 analogue, exenatide, an exenatide derivative, or an exenatide analogue. The description of the particular embodiments described for Table 1 is also applicable to the formulations described in Table 2.

Table 2 Within these ranges of percent by weight for the components of the particle formulation, some More preferred component proportions are the following: drug to one or more additional components (e.g., stabilizers in ratios of 1: 4, 1: 3, 1: 2, 1: 1, 2; 1, 2.5: 1, 5: 1, 10: 1.16: 1 and 20: 1, preferably between about 1: 4 and 10: 1 (for example, from about 1 to 10: 4 to 1), or preferably between about 1: 3 to 5: 1 (for example, from 1 to 5: 3 to 1) The present invention also includes ranges corresponding to all these drugs at proportions of the additional components (e.g., stabilizer ratios), e.g., between about 1: 1 and 2. : 1 (for example, from 1 to 2: 1) between about 1: 4 and about 20: 1 (for example, about 1 to 20: 4 to 1), between about 1: 4 and about 20: 1 (per example, from about 16: 4 to 1), between about 1: 4 and about 16: 1 (for example, from 1 to 16: 4 to 1), between about 1: 3 and about 10: 1 (for example , of approximation e 1 to 10: 3 to 1) between about 1: 2 and about 20: 1 (e.g., from about 1 to 20: 2 to 1) and so on.

Accordingly, in one aspect of the present invention it includes a formulation of particles comprising from about 25% by weight to about 80% by weight, preferably from about 40% by weight to about 75% by weight of the drug and about 75% by weight to about 20% by weight, preferably from about 60% by weight to about 25% by weight of one or more additional components, for example, stabilizers selected from the group consisting of antioxidants, carbohydrates and regulators , wherein the ratio of the drug: antioxidant: carbohydrates: regulator is between about 2 to 20: 1 to 5: 1 to 5: 1 to 10, preferably between about 5 to 10: 1 to 2.5: 1 to 2.5: 1 to 5 Generally, the particle formulations of the present invention comprise less than about 10% by weight, and preferably less than about 5% by weight of residual moisture.

An example of a particle formulation of the present invention includes, but is not limited to, the protein a drug, methionine as an antioxidant, sucrose, a carbohydrate and citrate a regulator, wherein the protein constitutes between about 40% by weight and about 70% by weight of the particle formulation and the proportion of protein to additional components is between about 1: 2 and 3: 1 (eg, from about 1 to 3: 2 to 1). The specific proteins exemplified below include an interferon and an incretin mimic (Example 1).

In summary, a selected drug or combination of drugs is formulated in a dry powder in the solid state, which preserves the maximum chemical and biological stability of the drug. The particle formulation offers stability in long-term storage at high temperature therefore allows administration to a subject of a biologically and stable effective drug for extended periods of time. In one embodiment, the peptides, polypeptides or protein are highly concentrated drug particle formulations of the present invention, are stable for transport and / or storage without the requirement of refrigeration or freezing. In the absence of the stabilization provided by the highly concentrated drug particle formulations of the present invention, the peptides, polypeptides and proteins may be unstable for transport and / or storage or may otherwise require cold or frozen conditions for transport and storage. For example, a highly concentrated drug particle formulation placed in a sterile vial or vial. At the time of use, the particle formulations of the present invention can be rapidly reconstituted with, for example, water for injection to create a highly concentrated aqueous solution just prior to administering a bolus injection to a subject.

The particle size distribution of dry powder can be well controlled (0.1 microns at 20 microns), example, using the methods of spray drying or lyophilization to prepare the particle formulations. The process parameters for dry powder formation are optimal for producing particles with the desired particle size distribution, density and surface area.

The selected excipients and regulators in the formulation of highly concentrated drug particles can provide, for example, the following functions: modification of the density of the dry powder, preservation of the chemical stability of the drug; maintenance of the physical stability of the drug (for example, high glass transition temperature, and avoiding the transition from phase to phase); produce homogeneous suspension dispersions; modifying the hydrophobicity and / or hydrophilicity to manipulate the solubility of the dry powder in selected solvents; and pH manipulation during the processing and maintenance of the pH in the product (for solubility and stability). 3. 2.0 Formulation of the Vehicle and Formulations of Suspension.

In one aspect of the present invention, the suspension vehicle provides a stable environment in which the highly concentrated drug particle formulation is dispersed. The highly concentrated drug particle formulations are chemically stable and physically (as described above) in the suspension vehicle. The suspension vehicle generally comprises one or more polymers and one or more solvents that form a solution of sufficient viscosity to uniformly suspend the particles comprising the drug. The suspension vehicle may comprise additional components, including but not limited to, surfactants, antioxidants and / or other soluble compounds in the vehicle.

The viscosity of the suspension vehicle is generally sufficient to prevent the highly concentrated drug particle formulations from settling during storage and use in a method of administration, for example, in an implantable drug delivery device. The suspension vehicle is biodegradable because the suspension vehicle disintegrates or decomposes in a period of time in response to a biological environment, while the highly concentrated drug particle is dissolved in the biological environment, and the active pharmaceutical ingredient in particle is absorbed.

The solvent in which the polymer is dissolved can affect the characteristics of the suspension formulation, such as the behavior of the formulation of highly concentrated drug particles during storage. A solvent can be selected in combination with a polymer so that the resulting suspension vehicle exhibits phase separation upon contact with the aqueous environment. In some embodiments of the invention, the solvent may be selected in combination with the polymer so that the resulting suspension vehicle exhibits phase separation upon contact with the aqueous environment having less than about 10% water.

The solvent may be an acceptable solvent that is not miscible in water. The solvent can also be selected so that the polymer is soluble in the solvent in high concentrations, such as in the concentration of polymers greater than about 30%. Examples of solvents useful in the practice of the present invention include, but are not limited to, lauryl alcohol, benzyl benzoate, benzyl alcohol, lauryl lactate, decanol (also called decyl alcohol), ethylexyl lactate, aliphatic alcohols of long chain (C8 to C24), esters, or mixtures thereof. The solvent used in the suspension vehicle can be "dry" because it has a low moisture content. Preferred solvents for use in the formulation of the suspension vehicle include lauryl lactate, lauryl alcohol, benzyl benzoate and mixtures thereof.

Examples of polymers for the formulation of suspension vehicles of the present invention include, but are not limited to, polyester (e.g., polylactic acid or polylactic polyglycolic acid); a polymer comprising pyrrolidones (e.g., polyvinylpyrrolidone (PVP) having a molecular weight range from about 2,000 to about 1,000,000), ester or ether of a saturated alcohol (e.g., vinyl acetate); polyoxyethylene-polyoxypropylene block copolymer, or mixtures thereof. In one embodiment, the polymer is PVP having a molecular weight of 2,000 to 1,000,000. In a preferred embodiment of the polymer is polyvinylpyrrolidone K-17 (which generally has a range of average molecular weight of about 7,900 to 10,800). Polyvinylpyrrolidone can be characterized by its K-value (for example, K-17) which is a viscosity index. The polymer used in the suspension vehicle may include one or more different polymers or may include different grades of a single polymer. The polymers used in the suspension vehicle can also be dry or have a low moisture content.

Generally speaking, a suspension vehicle according to the present invention may vary in its composition based on the desired performance characteristic. In one embodiment, the suspension vehicle may comprise from about 40% by weight to about 80% by weight of polymers and from about 20% to about 60% by weight of polymers. weight of solvents. Preferred embodiments of a suspension vehicle include vehicles formed of polymer and solvents combined in the following proportions: about 25% by weight of solvent and about 75% by weight of polymer; about 50% by weight of the solvent and about 50% by weight of the polymer; and about 75% by weight of the solvent and about 25% by weight of the polymer. Accordingly, in some embodiments the suspension vehicle may comprise selected components and in other embodiments consists essentially of selected components.

The suspension vehicle may exhibit a Newtonian behavior. The suspension vehicle is generally formulated to produce a viscosity that maintains a uniform dispersion of the particle formulation for a predetermined period of time. This helps to facilitate the manufacture of a suspension formulation designed to produce the controlled administration of the drug contained in the formulation of highly concentrated drug particles. The viscosity of the suspension vehicle may vary depending on the desired application, the size and type of the particle formulation and the loading of the particle formulation in the suspension vehicle. The viscosity of the suspension vehicle can be varied by altering the type or relative amount of the solvent or polymer used.

The suspension vehicle can have a viscosity range of about 100 poises to about 1,000,000 poises. Preferably from about 1,000 to about 100,000 poises. In preferred embodiments, suspension vehicles generally have a viscosity, at a temperature of 33 ° C, of between about 5,000 and about 30,000 poises, preferably between about 8,000 and about 25,000 poises, more preferably between about 10,000 and about 20,000 poises. In one embodiment, the suspension vehicle has a viscosity of about 15,000 poises plus or minus 3000 poise, at a temperature of 33 ° C. The viscosity can be measured at a temperature of 33 ° C, at a cut-off index of 10"4 / second, using a parallel plate rheometer.

The suspension vehicle may exhibit phase separation when contacted with the aqueous environment, however, generally the suspension vehicle does not substantially exhibit phase separation as a function of temperature. For example, at a temperature in the range of about 0 ° C to about 70 ° C and at the time of temperature cycling, such as cycling from 4 ° C to 37 ° C to 4 ° C, the suspension vehicle generally does not exhibit phase separation.

The suspension vehicle can be prepared by combining the polymer and the solvent under dry conditions, such as in a dry box. The polymer and the solvent can be combined at elevated temperatures, such as from about 40 ° C to about 70 ° C, and can be allowed to become liquid and form a single phase. The ingredients can be mixed under vacuum to eliminate the air bubbles produced from the dry ingredients. The ingredients can be combined using a conventional mixer, such as a dual blade blade mixer or the like, prepared at a speed of about 40 rpm. However, higher speeds can also be used to mix the ingredients. Once the liquid solution of the ingredients is achieved, the suspension vehicle can be cooled to room temperature. Differential scanning calorimetry (DSC) can be used to verify that the suspension vehicle is single-phase. In addition, vehicle components (e.g., solvent and / or polymer) can be treated to substantially reduce or remove the peroxides substantially (e.g., by methionine treatment; see, e.g., the Patent Publication Application. North American No. 2007-0027105).

The formulation of highly concentrated drug particles is added to the suspension vehicle to form a suspension formulation. In some embodiments, the suspension formulation may comprise a formulation of highly concentrated drug particles and a suspension vehicle and in other embodiments consists essentially of a formulation of highly concentrated drug particles and a suspension vehicle.

The suspension formulation can be prepared by dispersing the particle formulation in the suspension vehicle. The suspension vehicle can be heated and the particle formulation added to the suspension vehicle under dry conditions. The ingredients can be mixed under vacuum at an elevated temperature, such as from about 40 ° C to about 70 ° C. The ingredients can be mixed at a sufficient rate, such as from about 40 rpm to about 120 rpm, and for a sufficient amount of time, such as about 15 minutes, to achieve uniform dispersion of the particle formulation in the carrier vehicle. suspension. The mixer can be a double-blade blade mixer or other suitable mixer. The resulting mixture can be removed from the mixer, sealed in a dry container to prevent water from contaminating the suspension formulation, and can be allowed to cool to room temperature before use, for example, by loading it into a drug delivery device that it can be implanted, a unit dose container, or a multiple dose container.

The suspension formulation generally has a general moisture content of less than about 10% by weight, preferably less than about 5% by weight, and more preferably less than about 4% by weight.

The suspension formulations of the present invention are exemplified hereinafter with reference to an imitation of incretin and an interferon (Example 2). In addition, the stability of the drug particle formulations suspended in a vehicle that is biocompatible, single-phase, and non-aqueous are described in Example 3B. These examples are not intended to be limiting.

In summary, the components of the suspension vehicle provide biocompatibility. The components of the suspension vehicle offer suitable chemical-physical properties to form stable suspensions of highly concentrated drug particle formulations. These properties include, but are not limited to, the following: viscosity of the suspension; purity of the vehicle; residual moisture of the vehicle; vehicle density; compatibility with dry powders; compatibility with devices that can be implanted; molecular weight of the polymer; stability of vehicle; and hydrophobicity and hydrophilicity of the vehicle. These properties can be manipulated and controlled, for example, by varying the composition of the vehicle and by manipulating the proportion of components used in the suspension vehicle. 4. 0.0 Administration of Suspension Formulations The suspension formulations described herein can be used in a drug delivery device that can be implanted to provide sustained administration of a compound for a prolonged period of time, such as weeks, months, or even about one year, for example, at least about 1 month, at least about 1.5 months, preferably at least about 3 months, preferably at least about 6 months, more preferably at least about 9 months months, and more preferably at least about 12 months. Such an implantable drug delivery device generally has the ability to deliver the compound in a desired flow range for a desired period of time. The suspension formulation can be loaded into the drug delivery device which can be implanted by conventional techniques.

The suspension formulation can be administered, for example, by using a drug delivery device operated osmotically, mechanically, electromechanically, or chemically. The formulation of highly concentrated drug particles is administered in a flow range that delivers a drug that is therapeutically effective to the subject in need of treatment of said drug.

The drug can be administered for a period of time in a range from more than about one week to about one year or more, preferably from about one month to about a year or more, even more preferably from about three months to about a year or more. plus. The implantable drug delivery device can include a container having at least one hole through which the drug is administered. The suspension formulation can be stored inside the container. In one embodiment, the drug delivery device that can be implanted is an osmotic delivery device, wherein the administration of the drug is osmotically operated. Some osmotic delivery devices and their component parts have been described, for example, the DUROS® delivery device or similar devices (see, for example, U.S. Patent Nos. 5,609,885, 5,728,396, 5,985,305, 5,997,527, 6,113,938; 6,132,420; 6,156,331; 6,217,906; 6,261,584; 6,270,787; 6,287,295; 6,375,978; 6,395,292; 6,508,808; 6,544,252; 6,635,268; 6,682,522; 6,923,800; 6,939,556; 6,976,981; 6,997,922; 7,014,636; 7,207,982; 7,112,335; 7,163,688; US Patent Publications Nos. 2005-0 75701, 2007-0281024, and 2008-0091176).

The DUROS® delivery device generally consists of a cylindrical container which contains the osmotic machine, a piston, and the drug formulation. The container is capped at one end by a controlled amount of semipermeable membrane and capped at the other end by a diffusion moderator through which the drug formulation of the drug container is released. The piston separates the drug formulation from the osmotic machine and uses a seal to prevent water from the osmotic machine compartment from entering the drug container. The diffusion moderator is designed, in conjunction with the drug formulation, to prevent body fluid from entering the drug container through the orifice.

The DUROS® device releases a drug in a predetermined amount based on the principle of osmosis. The extracellular fluid enters the DUROS® device through a semipermeable membrane directly into a salt machine that expands to operate the piston in a slow and balanced administration. The movement of the piston forces the formulation of the drug to be released through the orifice or port of exit at a predetermined cutoff index. In one embodiment of the present invention, the container of the DUROS® device is loaded with a suspension formulation of the present invention, comprising a formulation of highly concentrated drug particles, wherein the apparatus has the ability to deliver the suspension formulation a subject for a prolonged period of time (e.g., about 1, about 3, about 6, or about 12 months) in a previously determined, therapeutically effective amount of administration.

The devices that can be implanted, for example, the DUROS® device, provide the following advantages for the administration of a formulation of highly concentrated drug particles: real zero-order release of the pharmacokinetically beneficial agent; long-term release time period (for example, up to approximately 12 months); patient compliance; and reliable administration and dosing of a drug.

Other drug delivery devices that can be implanted can be used in the practice of the present invention and can include regulator-type implantable pumps that provide a constant flow, adjustable flow, or programmable flow of the compound, such as those that are available in Codman & Shurtleff, Inc. (Raynham, MA), Medtronic, Inc. (Minneapolis, MN), and Tricumed Medinzintechnik GmbH (Germany).

The amount of the highly concentrated drug particle formulation employed in the delivery device of the present invention is that amount necessary to deliver a therapeutically effective amount of the agent to achieve the desired therapeutic result. In practice, this will vary depending on such variables, for example, as the particular agent, the site of administration, the severity of the condition, and the desired therapeutic effect. Examples of the approximate release amounts of the example highly concentrated drug particle formulations of the present invention are presented in Example 4, including the release amounts for exenatide (Figure 2, Figure 3, and Figure 5) and the release amounts of interferon omega (figure 1 and figure 4).

The data presented in Figure 4 and Figure 5 illustrate another aspect of the present invention, wherein the highly concentrated drug particles of the present invention can be used in a method to control the amount of release of a drug by varying the percentage by weight of the drug. weight of the charged particles in the suspension formulation, the concentration of the drug in the particle formulation, or both. Said method is useful for preparing osmotic delivery devices that can deliver customizable concentrations of the drug over time, wherein a series of material particle formulations covering a range of particles / drug concentrations can be used individually. or in combination in a range of particle loading concentrations to produce the administration of a selected concentration of the drug over time. This allows manufacturing efficiencies to prepare different dosing regimens and even provide customized dosing of individuals, for example, weight. Therefore, different dosage levels can be provided as needed.

Generally, for an osmotic delivery device, the volume of a chamber of the beneficial agent comprising the beneficial agent formulation is between about 100 μ? up to about 1000 μ ?, more preferably between about 120 μ? and about 500 μ ?, and more preferably between about 150 μ? and approximately 200 μ ?.

Generally, the osmotic delivery device is implanted within the subject, for example, subcutaneously. The devices can be inserted subcutaneously into either or both arms (e.g., inside, outside, or the back of the upper arm) or the abdomen. The preferred locations in the abdomen are under the abdominal skin in the area that extends below the ribs and above the belt line. To provide a number of locations for the insertion of one or more osmotic delivery devices into the abdomen, the abdominal wall can be divided into 4 quadrants as follows: the right upper quadrant extends 5 to 8 centimeters below the ribs Right and approximately 5 to 8 centimeters to the right of the midline, the right lower quadrant extends 5 to 8 centimeters above the belt line and 5 to 8 centimeters to the right of the midline, the upper quadrant left extends from 5 to 8 centimeters below the left ribs and approximately 5 to 8 centimeters to the left of the midline, and the left lower quadrant extends from 5 to 8 centimeters above the belt line and from 5 to 8 8 centimeters to the left of the middle line. This provides multiple locations available for the implant of one or more devices on one or more occasions.

Suspension formulations of the present invention comprising highly concentrated drug particle formulations can also be administered from a drug delivery device that is not implantable or implanted, for example, an external pump such as a peristaltic pump used for administration subcutaneous in a hospital setting.

The suspension formulations of the present invention can also be used in infusion pumps, for example, the osmotic pumps ALZET® (DURECT Corporation, Cupertino CA) which are miniature infusion pumps, for the continuous dosing of laboratory animals (for example, mice and rats).

The suspension formulations of the present invention can also be used in the form of injections to produce highly concentrated bolus doses of the drug.

Some advantages and benefits of the suspension formulations of the present invention administered by means of an osmotic delivery device, such as the DUROS® device, include, but are not limited to the following. Increased compliance with the treatment may result in improved efficacy and such increased compliance may be achieved using an implanted osmotic delivery device. The effectiveness of the treatment can be improved because the implantable osmotic delivery device, such as a DUROS® device, can produce continuous and consistent administration of the drug 24 hours a day. Also, unlike other sustained release formulations and depot injections, dosing the drug when using the DUROS® device can be immediately interrupted by removal of the device, for example, if a safety problem arises for a particular subject.

The present invention also includes methods of manufacturing the formulations of the present invention, including the particle formulations, suspension vehicles, and suspension formulations described hereinbefore. The present invention also includes methods of manufacturing osmotic delivery devices comprising, for example, loading a selected suspension formulation into a container of an osmotic delivery device. 5. 0.0 Uses of Suspension Formulation Suspension formulations as described herein provide promising alternatives to different therapies that require daily dosing of a selected drug. For example, suspension formulations of the present invention comprising highly concentrated incretin imitation particle formulations may be useful in the treatment of diabetes (e.g., diabetes mellitus, and gestational diabetes), and conditions related to diabetes ( example, diabetic cardiomyopathy, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly myocardial ischemia), as well as, hyperglycemia (due to example, related to treatment with medications that increase the risk of hyperglycemia, including beta blockers, thiazide diuretics, corticosteroids, niacin, pentamidine, protease inhibitors, L-asparaginase, and some antipsychotic agents), reducing food assimilation ( for example, treatment of obesity, appetite control, and weight reduction), attacks, decreased plasma lipids, acute coronary syndrome, hibernating myocardium, regulation of gastrointestinal mobility, and increased urinary flow.

In addition, the suspension formulations of the present invention can be potential appetite regulators in subjects treated with the formulations.

As another example, highly concentrated drug particle formulations comprise an interferon which may be useful for the treatment of diseases responsive to interferon, such as viral infections, immune conditions, and cancers. The treatment of such diseases that respond to interferon is generally carried out for a prolonged period of time. For example, omega interferon can be used for the treatment of viral infections, for example, flavivirus infections (e.g., hepatitis C, yellow fever, and West Nile; Buckwold, VE, and associates, in Antiviral Research 73: pages 118 to 125 (2007)). The lack of compliance with dosing programs has historically been a problem for such long-term treatments. Suspension formulations of the present invention when provided in, for example, osmotic delivery devices, produce a desirable alternative for daily injections.

In one embodiment, suspension formulations are administered using an osmotic delivery device as described above. The release amounts of the suspension formulations of the present invention provide osmotic delivery systems that consistently and uniformly administer the drug in a selected amount of administration for extended periods of time. Examples of achievement of the administration rates using the suspension formulations of the present invention are given in Example 4. Release rate data indicated that the systems administered the drug in a consistent and uniform manner in an approximate amount of administration of 50 ng / day for interferon (figure 1), an approximate amount of 75 μg / day for exenatide (figure 2), and an approximate amount of 80 μg / day for exenatide (figure 3).

The cut-off rate of the suspension formulation of the osmotic delivery device is determined such that the daily target administration rate of the drug is reasonably achieved by the uniform and substantially continuous administration of the suspension formulation of the delivery device. osmotic. Examples of output cut-off rates include, but are not limited to, from about 1 to about 1 X 107 reciprocal second, preferably from about 4 X 10"2 to about 6 X 10" 4 reciprocal second, and more preferably from 5 X 10"3 to 1 X 10" 3 second reciprocal. 6. 0.0 Osmotic Management Devices The highly concentrated drug particle formulations of the present invention can be administered, for example, using an osmotic delivery system. In one embodiment, the present invention relates to the use of osmotic delivery devices that are small in size relative to the osmotic delivery devices in current use. Figure 6B shows a schematic representation of an osmotic delivery system having the dimensions of approximately 45 mm in length and approximately 3.8 mm in diameter. Osmotic delivery devices of this size have been used for the administration of, for example, suspension formulations of interferon omega particles and suspension formulations of exenatide particles ("Continuous Administration of Stabilized Proteins and Peptides at Constant Rates by at Least Three Months from the DUROS® Device, "2008, American Association of Pharmaceutical Sciences, Board and Annual Exhibition, Poster No. T3150, November 18, 2008, Yang, B., and associates;" An One-Stage Study 1b from ITCA 650: Continuous Subcutaneous Administration of Exenatide by DUROS® Device Decreases Fasting and Glucose in Postprandial Plasma, "American Diabetes Association, 69th Scientific Session, June 5 to 9, 2009, Luskey, K., and associates; and "A One-Stage Study 1b of ITCA 650:" Continuous Subcutaneous Administration of the Exempt through the DUROS® Device Decreases Fasting and Glucose of Postprandial Plasma, "European Association for the Study of Diabetes, 45th Annual Meeting , September 29 to October 3, 2009, Luskey, K., and associates.) The highly concentrated drug particle formulations of the present invention facilitate the use of even smaller-sized osmotic delivery devices while still providing the capability for producing a continuous long-term administration of controlled amounts of the drug over time For example, Figure 6C shows a schematic representation of an osmotic delivery system having the dimensions of approximately 30 mm in length and approximately 3.8 mm in diameter .

By increasing the concentration of the drug in the drug particle formulation, the amount of the drug particle suspension formulation can be loaded into the osmotic delivery device being reduced, the flow rate of the drug particle suspension formulation can be reduced, and the size of the osmotic delivery device may also be reduced while maintaining the ability to produce continuous long-term administration of previously determined amounts of the drug over time.

The embodiments of the implantable osmotic delivery devices generally comprise the following components (see Figure 6A): an impermeable container, the inner walls thereof defining a lumen, a semipermeable membrane at the first end of the container, a first chamber with ability to contain an osmotic agent, a piston, a second chamber with the ability to contain a drug suspension formulation, and a diffusion moderator and orifice at a second end of the container. The first chamber is defined by a first surface of the semipermeable membrane and a first surface of an adjacent piston. The second chamber is defined by a second surface of the piston and a first surface of the diffusion moderator.

Figure 6A illustrates an example of the system of DUROS® administration useful in the practice of the present invention. In Figure 6A, the osmotic delivery device 10 is shown to comprise a container 12. An assembly of the piston 14 is placed in the lumen of the container and divides the lumen into two chambers. In this example, chamber 16 contains a formulation of the beneficial agent and chamber 20 contains a formulation of the osmotic agent. A semipermeable membrane 18 is placed at a distal end of the container, adjacent to the chamber 20 containing the osmotic agent formulation. A diffusion moderator 22 is placed in a coupling relationship of a distal end of the container 12, adjacent the chamber 16 containing a suspension formulation, comprising the drug. The diffusion moderator 22 includes an administration port 24. The diffusion moderator 22 may be any suitable flow device having an administration port. In this embodiment, the flow path 26 is formed between a threaded diffusion moderator 22 and the cords 28 formed on the inner surface of the container 12. In alternative embodiments, the diffusion moderator may, for example, (i) be embedded by pressure (or friction) through an opening and contacting the smooth inner surface of the container, or (ii) comprises two pieces with an outer shell constructed and accommodated to place it in an opening, an inner core inserted into the shell outer, and a flow channel having a defined spiral shape between the outer shell and the inner core (e.g., U.S. Patent Publication No.2007-0281024).

The fluid is imbibed in the chamber 20 through the semipermeable membrane 18. The formulation of the beneficial agent is supplied from the chamber 16 through the delivery port 24 in the diffusion moderator 22. The piston assembly 14 engages and seals against the inner wall of the container 12, thereby isolating the formulation of the osmotic agent in the chamber 20 and the fluid imbibed through the semi-permeable membrane 18 of the beneficial agent formulation in the chamber 16. In a stable condition, the formulation of The suspension is expelled through the delivery port 24 in the diffusion moderator 22 in an amount corresponding to the amount in which the external fluid is imbibed into the chamber 20 through the semipermeable membrane 18. That is, the device of administration DUROS® releases the drug in a predetermined amount based on the principle of osmosis. The extracellular fluid enters the DUROS® delivery device through the semi-permeable membrane directly into the osmotic machine that expands to operate the piston in a slow and consistent amount of travel. The movement of the piston forces the formulation of the drug to be released through the orifice of the diffusion moderator resulting in a substantial administration of stable condition for the drug.

The semipermeable membrane 18 can be in the form of a cap which is engaged elastically in sealing relationship with the inner surface of the container 12. In Figure 6A, shown having edges that serve to frictionally engage the semipermeable membrane 18 with the inside surface of the container 12.

The embodiments of osmotic delivery devices that are small in size generally comprise components similar to those described in relation to Figure 6A. The osmotic delivery devices currently in use generally have the dimensions shown in Figure 6B, ie, approximately 45 mm in length and approximately 3.8 mm in diameter. An osmotic delivery device having reduced size relative to the apparatuses currently in use is shown in Figure 6C as having the dimensions of approximately 30 mm in length and approximately 3.8 mm in diameter. A marker band (e.g., the laser marker band shown in Figure 6B and Figure 6C) is optional, and may be used, for example, to mark devices having different dosages or different suspensions of the drug to distinguish them between The devices can also be useful to help with the determination of the desired insertion orientation for the implant. An external groove (e.g., as shown in Figure 6B and Figure 6C) is also optional and is generally used to aid in identifying the end of the semipermeable membrane of the apparatus and determining the desired orientation of the orientation of the device. insertion of the device for the implant.

The containers of the osmotic delivery devices, which are small in size, of the present invention are generally made of a material impervious to the environment of use (eg, body fluids) and impermeable to the osmotic agent as well as to the suspension formulation of the drug Preferred materials for the container include, but are not limited to, titanium and titanium alloys. The example sizes of the container for the devices of the present invention include osmotic delivery devices having a general length of between about 35 mm and about 20 mm in length, preferably between about 30 mm and about 25 mm in length, and more preferably of about 28 mm to 33 mm in length, and a diameter of between about 8 mm and about 3 mm, and preferably a diameter of about 3.8 mm to 4 mm. In one embodiment, the osmotic delivery device has a length of about 30 mm and a diameter of about 3.8 mm.

Exemplary embodiments of the device components osmotic and materials used for manufacturing administration may be found, for example, in U.S. Patent Nos. 5,728,396, 6,113,938, 6,132,420, 6,270,787, 6,375,978, 6,544,252, 6,508,808, 5,997,527, 6,524,305, 6,287,295, 7,163,688, 7,074,423, 7,014,636, 6,939,556, 7,207,982, 7,241,457, 7,407,499, and Patent Publications North American Nos. 2005-0010196, 2005-0101943, 2005-0175701, 2007-0281024, 2008-0091176. Said components can be sized to produce osmotic delivery devices that are small in size in view of the teachings of the present disclosure.

In one embodiment, maintaining essentially the same diameter of the container between the larger and smaller osmotic delivery devices provides the advantage that the components of the two devices that are not the container (eg, the semipermeable membrane, the piston, and the diffusion moderator) can be manufactured in one size and the components used interchangeably between the two devices. In a similar way, a range of devices having a range of vessel lengths can be produced where the remaining components can be used interchangeably for the manufacture of multiple devices having different vessels of different length and therefore a volume different and a load capacity of the drug. 7. 0.0 Some Advantages of the Highly Concentrated Drug Particle Formulations of the Present Invention Particles that are highly concentrated with the active drug are useful for the preparation of osmotic delivery devices that can administer high doses of the drug while maintaining the overall size of the device small enough to be easily implanted and remain acceptable to the patient. Highly concentrated drug particle formulations can be particularly useful when high doses of the selected drug are required for the effective treatment of a disease or condition. In particular, highly concentrated drug particle formulations extend the utility and use of osmotic delivery devices for lower potency drugs that require doses generally considered too high for such devices; for example, proteins such as GLP-1, exenatide, PYY, oxyntomodulin, GIP, interferon (eg, alpha, beta, gamma, lambda, omega, tau, consensus, and variant interferons), antibodies, or small molecules such as testosterone or other steroids. The highly concentrated particles also facilitate the preparation of the high dose osmotic delivery devices that are necessary for dose ranges of study for both animal toxicology studies and for studies and initial dose discovery in humans.

Highly concentrated drug particles are also useful for the preparation of osmotic delivery devices that can administer therapeutic doses of a drug for a prolonged period of time. These are particularly useful for the treatment of chronic diseases and conditions such as diabetes and obesity where fewer device replacements are desired per year. Example 5 demonstrates that highly concentrated particles are useful for preparing implantable osmotic delivery devices that can deliver doses of a drug for extended periods of time at desired delivery rates.

In contrast, suspension formulations comprising the particle formulations contain relatively low concentrations of the active drug (less than about 20%) require high particle loads in order to achieve high daily dosage of the drug. Higher daily doses require higher weight percentages of the particles and can result in formulations that are difficult to pump reliably through the diffusion moderator of the apparatus. Said high particle charges may cause, for example, either the physical blockage of the outlet channel or pressures of sufficient internal apparatus to cause the semipermeable membrane ejection device to fail. Although a potential solution could be to increase the diameter of the outlet channel and / or decrease the length of the outlet channel, such strategies can allow the entry of moisture from the body fluids into the drug formulation chamber by means of the moderator of diffusion and results in either drug instability or physical instability of the suspension and possible device failure.

The highest concentration of the drug in the particles is useful to maintain the particle loads of about 30% or less, 20% or less, or preferably 10% or less of particles by weight relative to the weight of the suspension formulation complete Accordingly, the advantages of the highly concentrated drug particle formulations of the present invention include the ability to produce drugs in higher concentrations while maintaining lower particle loads in the suspension formulation due to the higher drug concentration. .

Highly concentrated drug particle formulations with higher concentrations of the active drug may also have the advantages for the production process and overall process performances. The production of said particles generally begins with a solution of the drug in water, followed by a drying step such as spray drying or lyophilization. Proteins, in particular, are not stable in aqueous solutions, therefore it is important to minimize the amount of time the drug is exposed to water. The higher concentrations of the drug in solution mean relatively lower amounts of water that must be removed in the drying process and thus a faster drying process. A faster drying process can be particularly important for the preparation of drug particles comprising drug molecules that are unstable at high temperatures and / or when exposed to moisture.

An additional benefit may be that the size of the particles formed by the faster drying process are smaller than the particles formed using the lowest concentration. Providing smaller particles further reduces the potential for obstruction of the outlet channel of the diffusion moderator and may facilitate the use of smaller channel diameters and / or lengths if required for the operational reliability of the particular osmotic delivery device / combinations of the formulation.

Another advantage of suspension formulations comprising highly concentrated drug particle formulations of the present invention is the ability to utilize reduced osmotic delivery devices for drug administration while maintaining the ability to produce long desired drug concentrations. term, for continuous administration. In one embodiment, the present invention relates to an osmotic delivery device having a general length of between about 35 mm and about 20 mm in length, preferably between about 30 mm and about 25 mm in length, and more preferably about 28 mm in length. mm up to 33 mm in length, and a diameter of between about 8 mm and about 3 mm, and preferably a diameter of about 3.8 mm to 4 mm. The osmotic delivery device can be loaded with the suspension formulations comprising highly concentrated drug particle formulations of the present invention. The advantages of using the osmotic delivery devices, which are small in size, of the present invention (against current osmotic delivery devices, for example, having the dimensions shown in Figure 6B) include, but are not limited to, ( i) ease of implantation and improved removal, (ii) a greater number of implantation sites possible (eg, on the lower side of the arms and throughout the abdominal area), and (iii) reduced psychological impact on patients with respect to the implant / removal of a foreign object.

In addition, the ability to utilize the suspension formulations comprising highly concentrated drug particle formulations of the present invention in a variety of different sizes of the osmotic delivery devices allows to design the size of the device in combination with the concentration of the drug in the suspension formulation to produce a broad adaptation of dosage forms, drug strength, and administration durations. For example, suspension formulations having the same concentration of the drug can be used for drug delivery devices for at least about 1 month, at least about 1.5 months, preferably at least about 3 months, preferably at least about 6 months, more preferably at least about 9 months, and more preferably at least about 12 months filling the containers in different volumes.

The advantages of the highly concentrated drug particle formulations of the present invention include improved drug stability that allows broad geographic distribution, for example, without refrigeration, and improved access to drugs that generally have little stability but are stabilized in the formulations of highly concentrated drug particles. The additional advantages of the suspension formulations comprising the highly concentrated drug particle formulations of the present invention include the ability to deliver more drugs in less volume, administer less of the non-drug components of the suspension formulation, improved compliance of the patient with long-lasting treatments, and possible reduced side effects of the drug (e.g., nausea and / or vomiting) due to the consistent administration of the drug without peaks and depressions of drug concentration.

Other objects may be appreciated by those skilled in the art when reviewing the following specifications and claims.

Experimental The following examples are set forth to provide those skilled in the art with a complete description of how to make and use the devices, methods, and formulas of the present invention, and are not intended to limit the scope of what the inventor considers to be the invention. Efforts have been made to ensure accuracy with respect to the numbers used (for example, quantities, temperatures, etc.) but some errors of the experiment and deviations should be taken into account. Unless otherwise indicated, the parts are parts by weight, the molecular weight is the average molecular weight, the temperature is in degrees Centigrade, and the pressure is at or near atmospheric pressure.

The compositions produced according to the present invention cover the specifications for the content and purity required for pharmaceutical products.

Example 1 Drug Particle Formulations Highly Concentrated This example describes the preparation of spray-dried particle formulations with high concentration of pharmaceutical ingredients (e.g., drugs). The formulations of the present invention extend the loading of the drug in the spray-dried powder formulations.

A. Formulation 1 - Interferon Omega A frozen solution in bulk of the interferon omega, 5 g / L, was thawed at a temperature of 2 ° C to 8 ° C and then 22 mM of sodium citrate buffer was added at a pH of 5.9. The solution was dialysed with the sodium citrate buffer to form a final solution with 14 mg / ml of interferon omega. Then the solution was formulated with sucrose, and methionine and was spray-dried using the Niro SD Micro spray drier adapted with a 0.5 L collection container. Pump power was 400 g / h, the atomizing gas was 2.3 kg / h, the atomizing gas was at room temperature, the inlet temperature of the process gas was 140 ° C and the process gas was 30 kg / h. The dry powder contained 35% omega interferon with a residual moisture content of 3.0%. The proportion of the components in this particle formulation is as follows: 2: 1: 2: 1 (interferon omega: methionine: sucrose: citrate regulator).

B. Formulation 2 Exempt An exenatide solution was prepared in the following manner: 2.5 g of exenatide was dissolved in a sodium citrate buffer at a pH of 5.8 to 6.0. The solution was dialyzed with a formulation solution with a regulating content of sodium citrate, sucrose, and methionine. The formulated solution was then spray dried using a Buchi 290 apparatus with a 0.7 mm nozzle, outlet temperature of 85 ° C, atomization pressure of 100 Psi (7.03 kg / cm2), solids content of 2%, and range flow rate of 2.8 ml / min. The dry powder contained 44.82% exenatide with a residual moisture of 3.8% and a density of 0.2329 g / ml. The proportion of the components of this particle formulation is 5: 1: 1.3.5 (exenatide: methionine: sucrose: citrate regulator).

The concentration of the drug in this particle formulation was 44.82% by weight.

C. Formulation 3 - Exempt An exenatide solution was prepared in the following manner: 13.7 g of exenatide were dissolved in 50 mM sodium citrate buffer at a pH of 6.0. The solution was dialyzed with a formulation solution with a regulating content of sodium citrate, sucrose, and methionine. The formulated solution was then spray dried using a Niro SD Micro drier dryer adapted with a 0.5 L collection container. Pump power was 400 g / h, atomizer gas was 2.3 kg / h , the atomizer gas was at room temperature, the inlet temperature of the process gas was 140 ° C and the process gas was 30 kg / h. The dry powder contained 41.24% exenatide with 4.13% residual moisture. The proportion of the components in this particle formulation is as follows: 5: 1: 1: 3.4 (exenatide: methionine: sucrose: citrate regulator).

The concentration of the drug in this particle formulation was 41.24% by weight.

D. Formulation 4- Interferon Omega The frozen omega interferon solution with an omega interferon concentration of 5 mg / mL was thawed at a temperature of 2 ° C to 8 ° C and the solution was then dialysed with a sodium citrate solution at a pH of 6.0 to form a solution with 14 mg / ml of interferon omega. Then the solution was formulated with sucrose, and methionine. The formulated solution was spray dried using a Buchi 290 apparatus with a 0.7 mm nozzle, outlet temperature of 80 ° C, atomization pressure of 100 Psi (7.03 kg / cm2), solids content of 2%, and range of flow of 2.8 ml / min. The dry powder contained 69% interferon omega with residual moisture of 4%. The proportion of the components in this particle formulation is as follows: 6.8: 1: 1: 1 (interferon omega: methionine: sucrose: citrate regulator).

The concentration of the drug in this particle formulation is 69% by weight (% by weight).

The formulations described in Example 1A to Example 1D are summarized in Table 3. In Table 3, the percentages by weight of the drugs (% by weight) were determined directly using an HPLC method, while the weight% of other components were based on calculations of the composition of the formulation and corrected based on a humidity of 0% by weight. Accordingly, the weight percentage of the components in the list is essentially 100%.

Table 3 * The citrate regulator for this particle formulation was formed by Sodium Citrate / Citric Acid.

E. Formulation 5 PYY A solution of PYY was prepared in the following manner: 1 g of PYY was dissolved in 25 mM of sodium citrate buffer at a pH of 5.0. The solution was dialyzed with a formulation solution with a regulating content of sodium citrate, sucrose, and methionine. Then the formulated solution was spray dried using a Buchi 290 Micro spray dryer with a 0.7 mm nozzle, 100 ° C exit temperature, 100 Psi atomization pressure (7.03 kg / cm2), 2% solids content , and flow range of 2.8 ml / min. The dry powder contained 27.6% PYY. The proportion of the components in this particle formulation is as follows: 1.8: 1.0: 2.2: 1.5 (PYY: methionine: sucrose: citrate regulator).

The concentration of PYY in this particle formulation was 27.6% by weight. In Table 4, the percentages by weight (% by weight) of the PYY were determined directly using an HPLC method, while the% by weight of other components were based on calculations of the elaboration of the formulations and corrected based on a humidity of the 0% by weight. Therefore, the percentages by weight of the components of the list add up to essentially 100%.

Table 4 * The citrate regulator for this particle formulation Sodium Citrate / Citric Acid.

F. Formulation 6 - Oxintomodulin A solution of oxyntomodulin was prepared as follows: 1 g of oxintomodulin was dissolved in 25 mM of sodium citrate buffer at a pH of 4.0. The solution was dialyzed with a formulation solution with a regulating content of sodium citrate, sucrose, and methionine. The formulated solution was then spray dried using a Buchi 290 Micro spray dryer with a 0.7 mm nozzle, 100 ° C exit temperature, 100 Psi atomization pressure (7.03 kg / cm2), 2% solids content , and flow range of 2.8 ml / min. The dry powder contained 43.3% oxyntomodulin.

The proportion of the components in this particle formulation is as follows: 4.1: 1.8: 1: 2.6 (oxintomodulina: methionine: sucrose: citrate regulator).

The concentration of oxintomodulin in this particle formulation was 43.3% by weight. In Table 5, the percentages by weight (% by weight) of oxyntomodulin were determined directly using an HPLC method, while the% by weight of other components were based on calculations of the preparation of the formulation and corrected based on moisture content of the formulation. 0% by weight. Therefore, the percentages by weight of the components of the list add up to essentially 100%.

Table 5 * The citrate regulator for this particle formulation Sodium Citrate / Citric Acid.

The data presented in Example 1 demonstrated that the particle formulations of the present invention make possible the production of highly concentrated drug particles.

Example 2 Suspension Formulations This example describes the preparation of suspension formulations comprising a suspension vehicle and the particle formulations of the present invention.

A. Formulation of Suspension 1 - Interferon Omega The particle formulation was prepared as described in Example 1, Formulation 1.

A suspension vehicle was formed by dissolving the polyvinylpyrrolidone polymer in the benzyl benzoate solvent in approximately a 50:50 weight ratio.

The viscosity of the vehicle was approximately 12,000 18,000 poises when measured at a temperature of 33 ° C.

The particles containing the 35% omega interferon were dispersed in the vehicle at a concentration of 8.13% by weight of particles in relation to the total weight of the suspension formulation.

B. Formulation of Suspension 2 The particle formulation was prepared as described in Example 1, Formulation 2.

A suspension vehicle was formed by dissolving the polyvinylpyrrolidone polymer in the benzyl benzoate solvent in a proportion of about 50:50 by weight. The viscosity of the vehicle was 12,000 to 18,000 poise when measured at a temperature of 33 ° C. The particles containing 44.82% exenatide were dispersed in the vehicle at a concentration of 11.2% by weight of particles relative to the total weight of the suspension formulation.

C. Formulation of Suspension 3 The particle formulation was prepared as described in Example 1, Formulation 3.

A suspension vehicle was formed by dissolving the polyvinylpyrrolidone polymer in the benzyl benzoate solvent in a proportion of about 50:50 by weight. The viscosity of the vehicle was approximately 12,000 to 18,000 poise when measured at a temperature of 33 ° C. The particles containing 41.24% exenatide were dispersed in the vehicle at a concentration of 12% by weight of particles relative to the total weight of the suspension formulation.

The Formulation of Particles 1 to 3, described in Example 1, were dispersed in the vehicle in a concentration (% by weight) shown in Table 6.

Table 6 Formulation Formulation Formulation Formulation Suspension 1 Suspension 2 Suspension 3 (% by weight) (% by weight) (% by weight) Formulation of Particles 8.13 11.2 12 Polymer 45.94 44.4 44 (Polyvinylpyrrolidone) Solvent 45.94 44.4 44 (Benzyl benzoate) D. Additional Suspension Formulations The particle formulations were prepared as described in Example 1. The exenatide particle formulation was described in Example 1, Formulation 3.

A suspension vehicle was formed by dissolving the polyvinylpyrrolidone polymer in the benzyl benzoate solvent in a proportion of about 50:50 by weight. The viscosity of the vehicle was approximately 12,000 to 18,000 poise when measured at a temperature of 33 ° C. The particles, as described in Example 1, were dispersed in the vehicle at a concentration shown in Table 7. The concentration of particles is given in relation to the total weight of the suspension formulation.

The Formulations of particles 3, 5 and / or 6 described in Example 1 were dispersed in the vehicle in the concentrations (% by weight) shown in Table 7.

Table 7 "oxintomodulin; ** exenatide, *** (proportion of particles) The data presented in Example 2 demonstrated that the highly concentrated drug particle formulations of the present invention make possible the production of suspension formulations for pharmaceutical use.

Example 3 Stability of the Drug in Particle Formulations and Suspension Formulations A. Stability of the Particle Formulation A study was conducted to evaluate the stability of the particle formulation as a spray-dried powder. The samples were analyzed by Size Exclusion Chromatography (SEC) and Reverse Phase High Performance Liquid Chromatography (RP-HPLC). The results are shown in Table 8.

Table 8 * ND = not determined.

The purity data based on the SEC and RP-HPLC analyzes demonstrated excellent stability for the highly concentrated drug particle formulations of the present invention.

B. Stability of the Suspension Formulation A study was conducted to evaluate the stability of drug particle formulations suspended in a vehicle that is biocompatible. of a single phase, and not watery. For the analytical test, the omega interferon or exenatide was extracted from the suspension with an extraction solvent and the samples were analyzed using Size Exclusion Chromatography (SEC), Reverse Phase High Performance Liquid Chromatography (RP-HPLC), and bioassays.

The extraction solvent dissolved the suspension vehicle and precipitated the drug. The precipitate of the drug was washed several times, dried, and then reconstituted in water for analysis. The monomeric and aggregated forms of interferon omega were separated by the SEC method using a Super SW2000 column of TSK-Gel and detected with a UV detector at 220 nm. The purity and identity of the interferon omega were determined by RP-HPLC on a RP-HPLC Zorbax 300SB-C8 column, at an acid pH and with a UV detection at 220 nm.

The monomeric and aggregated forms of exenatide were separated by the SEC method using the Super SW2000 column of TSK-Gel and detected with the UV detector at 220 nm. The purity and identity of the exenatide were determined by RP-HPLC in the CLIPEUS-C8 column of Higgins, at an acidic pH and with a UV detection at 210 nm.

The suspension formulations that loaded the target particles are shown in Table 8. The implantable osmotic delivery device (e.g., DUROS® delivery device), the containers were filled with the volume of the suspension shown in FIG. Table 9 and stored at a temperature of 25 ° C and 40 ° C. Several samples were extracted and analyzed at initial and subsequent time points as shown in Table 9. Monomer levels were measured by SEC and purity levels were measured by RP-HPLC. The results of the analysis are presented in Table 9.

Table 9 * ND = not determined.

The low level of the degradation products, as shown by the proportion of aggregated monomeric forms where the monomeric forms dominated, and the purity analysis showed that the suspension formulations, comprising the highly concentrated drug particle formulations of the present invention, provide excellent stability and purity of the drug.

Example 4 Release rates A study was conducted to evaluate the release rate of the suspension formulations according to the embodiments of the present invention using an implantable osmotic delivery device. For each study, a drug container of an osmotic delivery device that can be implanted with 160 μ? Was filled. of one of the suspension formulations described in Example 2. The ends of the membranes of the osmotic pumps were placed in corked glass jars filled with 3 ml of phosphate buffer solution (PBS), and the ends of the diffusion moderator of the osmotic pumps were placed in glass jars filled with 2.5 ml to 3 ml of release rate medium (citrate buffer solution at a pH of 6.0 with 0.14 M NaCl and 0.2% sodium azide).

Each system was placed in a capped test tube, with the diffusion moderator turned down, and partially immersed in a water bath at a temperature of 37 ° C. At the specified time points, the glass bottles at the ends of the diffusion moderator were replaced by new glass bottles filled with 2.5 ml to 3 ml release rate medium (citrate buffer solution at a pH of 6.0 with NaCl 0.14 M and 0.2% sodium azide). Samples were collected from the extremes of the diffusion moderator of the osmotic pumps and analyzed using RP-HPLC.

The results of the in vitro release index by RP-HPLC analysis are presented in Figure 1, Figure 2, and Figure 3. Figure 1 presents the data for the Suspension Formulation 1. The data shows the rate of release by day of 100 days at a temperature of 37 ° C with an approximate release rate of 50 μg / day. Figure 2 presents the data for the Suspension Formulation 2. The figure shows the release rate per day of 110 days at a temperature of 37 ° C with an approximate release rate of 75 g / day. Figure 3 presents the data for the Suspension Formulation 3. The figure shows the release rate per day of 100 days at a temperature of 37 ° C with an approximate release rate of 80 μg day. The horizontal lines across the data points illustrate the substantial administration of stable condition of the drugs at previously determined release rates.

The release index data indicates that the systems administer the drugs in a consistent and uniform manner close to the approximate 50 g / day ratio of interferon omega for Suspension Formulation 1, the approximate 75 Exenatide Index for the Suspension Formulation. 2, and the approximate index of 80 of Exenatida for the Formulation of Suspension 3.

Release rates for additional suspension formulations for a range of drug administration concentrations were also determined. The results of these in vitro release rates by RP-HPLC analysis are presented in Figure 4 and Figure 5. Figure 4 presents the data for the in vitro release of the osmotic delivery devices that can be implanted for interferon omega. The omega interferon particles and suspension formulations were prepared essentially as described above. The rate of release was controlled by varying the charge of particles in the suspension formulation or the concentration of the drug in the particles of the particle formulation or both. The data show the rate of release per day per 100 days at a temperature of 37 ° C with approximate release rates of 10, 25, 30, and 50 The horizontal lines across the data points illustrate the substantial administration of stable condition of the drugs at previously determined release rates.

Figure 5 presents data for the in vitro release of osmotic delivery devices that can be implanted for exenatide. The exenatide particles and suspension formulations were prepared essentially as described above. The rate of release was controlled by varying the charge of particles in the suspension formulation or concentration of the drug in the particles of the particle formulation or both. The data show the rate of release per day for 110 days at a temperature of 37 ° C with approximate release rates of 5, 10, 20, 40, and 75 μ9 ^? 8. The horizontal lines in the data points illustrate the substantial administration of stable condition of the drugs in the previously determined release rates.

The release index data shown in Figure 4 and Figure 5 further demonstrated that the osmotic delivery systems administer the drug continuously, consistently and uniformly close to the previously selected administration ranges using the particle and suspension formulations of the present invention. .

In summary, these data demonstrated that suspension formulations, comprising the highly concentrated drug particle formulations of the present invention, provide consistent and uniform drug administration at previously selected administration rates.

Example 5 Drug Administration rates. Quantities and periods of use The data presented in Table 10 demonstrated that highly concentrated particles are useful for preparing implantable osmotic delivery devices that can deliver doses of a drug for extended periods of time at defined administration rates.

Table 10 As those skilled in the art will appreciate, various modifications and variations may be made to the above embodiments without departing from the spirit and scope of the present invention. Said modifications and variations are within the scope of the present invention.

Claims (43)

1. A particle formulation comprising: from about 25% by weight to about 80% by weight of the drug; Y from about 75% by weight to about 20% by weight of one or more additional components, characterized in that the proportion of the additional drug component is between about 1: 1 to about 5: 1.

2. The particle formulation as described in claim 1, characterized in that the drug comprises from about 40% by weight to about 75% by weight and the one or more additional components comprising from about 60% by weight to about 25% by weight.

3. The particle formulation as described in claim 1 or claim 2, characterized in that the one or more additional components are selected from the group consisting of antioxidants, carbohydrates, and regulators.

4. The particle formulation as described in any of the preceding claims, characterized in that the one or more additional components comprise an antioxidant and the antioxidant is selected from the group consisting of cysteine, methionine, and tryptophan.

5. The particle formulation as described in claim 4, characterized in that the antioxidant is methionine.

6. The particle formulation as described in any of the preceding claims, characterized in that the one or more additional components comprise a regulator and the regulator is selected from the group consisting of citrate, histidine, succinate, and mixtures thereof.

7. The particle formulation as described in claim 6, characterized in that the regulator is a citrate.

8. The particle formulation as described in any of the preceding claims, characterized in that the one or more additional components comprise a carbohydrate and the carbohydrate is a disaccharide.

9. The particle formulation as described in claim 8, characterized in that the disaccharide is selected from the group consisting of lactose, sucrose, trehalose, cellobiose, and mixtures thereof.

10. The particle formulation as described in claim 9, characterized in that the disaccharide is sucrose.

11. The particle formulation as described in any of the preceding claims, characterized in that the one or more additional components comprise an antioxidant, carbohydrate, and regulator, and the ratio of drugs: antioxidant: carbohydrate: regulator is between about 2 to 20: from 1 to 5: from 1 to 5: from 1 to 10.

12. The particle formulation as described in any of the preceding claims, characterized in that the particle formulation is a spray-dried particle preparation.

13. The particle formulation as described in any of the preceding claims, characterized in that the drug is a protein.

14. The particle formulation as described in claim 13, characterized in that the protein is an interferon.

15. The particle formulation as described in claim 14, characterized in that the interferon is selected from the group consisting of consensus interferon, interferon alpha, interferon beta, interferon gamma, interferon tau, interferon omega, and mixtures thereof.

16. The particle formulation as described in claim 13, characterized in that the protein is an incretin imitation.

17. The particle formulation as described in claim 16, characterized in that the incretin mimic is a glucagon-1 like peptide (GLP-1), a GLP-1 derivative, or a GLP-1 analogue.

18. The particle formulation as described in claim 17, characterized in that the incretin mimic is GLP-1 (7-36) amide.

19. The particle formulation as described in claim 16, characterized in that the mimic of incretin is exenatide, an exenatide derivative, or an exenatide analogue.

20. The particle formulation as described in claim 19, characterized in that the mimic of incretin is exenatide.

21. The particle formulation as described in claim 13, characterized in that the protein is selected from the group consisting of exenatide, PYY, GLP-1 (7-36) amide, oxyntomodulin, GIP, and leptin.

22. The particle formulation as described in claim 13, characterized in that the protein is selected from the group consisting of recombinant antibodies, antibody fragments, humanized antibodies, single chain antibodies, monoclonal antibodies, and avimers.

23. The particle formulation as described in claim 13, characterized in that the protein is selected from the group consisting of human growth hormone, epidermis growth factor, fibroblast growth factor, platelet derived growth factor, factor of transformation growth, and nerve growth factor.

24. The particle formulation as described in claim 13, characterized in that the protein is a cytokine.

25. The particle formulation as described in any of the preceding claims, characterized in that the particles of the particle formulation are particles of between about 2 microns about 10 microns.

26. A suspension formulation which comprises: a particle formulation as described in any of the preceding claims; Y a non-aqueous single phase suspension vehicle comprising one or more polymers and one or more solvents; characterized in that the suspension vehicle exhibits viscous fluid characteristics, and the particle formulation is dispersed homogeneously in the vehicle.

27. The suspension formulation as described in claim 26, characterized in that the one or more polymers is a polymer comprising pyrrolidones.

28. The suspension formulation as described in claim 27, characterized in that the one or more polymers is polyvinylpyrrolidone.

29. The suspension formulation as described in any of claims 26 to 28, characterized in that the one or more solvents are selected from the group consisting of lauryl lactate, lauryl alcohol, benzyl benzoate, and mixtures thereof.

30. The suspension formulation as described in claim 26, characterized in that the suspension vehicle consists essentially of one or more polymers and one or more solvents.

31. The suspension formulation as described in claim 30, characterized in that the one or more solvents consist essentially of benzyl benzoate.

32. The suspension formulation as described in claim 30 or claim 31, characterized in that the one or more polymers consist essentially of polyvinylpyrrolidone.

33. The suspension formulation as described in claim 30, characterized in that the suspension vehicle consists essentially of benzyl benzoate and a polymer comprising pyrrolidones.

34. The suspension formulation as described in any of claims 26 to 33, characterized in that the suspension vehicle is about 50% solvent and about 50% polymer.

35. The suspension formulation as described in any of claims 26 to 34, characterized in that the suspension vehicle has a viscosity of about 15,000 poises, plus or minus about 3,000 poises.

36. An osmotic delivery device, which comprises the suspension formulation as described in any of claims 26 to 35.

37. The osmotic delivery device as described in claim 36, characterized in that the osmotic delivery device comprises a container having the dimensions of between about 35 mm and about 20 mm in length and about 8 mm and about 3 mm in diameter .

38. The osmotic delivery device as described in claim 37, characterized in that the container has the dimensions of between about 30 mm and about 25 mm in length and about 4 mm to about 3.8 mm in diameter.

39. A method of manufacturing an osmotic delivery device which comprises: loading the suspension formulation as described in any of claims 26 to 35 in a container of the osmotic delivery device.

40. The method as described in claim 39, characterized in that the osmotic delivery device comprises a container having the dimensions of between about 35 mm and about 20 mm in length and about 8 mm and about 3 mm in diameter.

41. The method as described in claim 40, characterized in that the container has the dimensions of between about 30 mm and about 25 mm in length and about 4 mm to about 3.8 mm in diameter.

42. A pharmaceutical formulation, which comprises the formulation of particles as described in any of claims 1 to 25.

43. A pharmaceutical formulation, which comprises the suspension formulation as described in any of claims 26 to 35.